CH624835A5 - Method for sweetening substances - Google Patents

Description

The present invention relates to a method for sweetening substances and to sweeteners for carrying out the method.

Products which are intended to be swallowed during normal use, for example a food or drink or an orally administered pharmaceutical preparation, are referred to as “digestible products”. An “oral agent” is an agent that should not be digested as such in normal use, but is used in the mouth to treat the throat or oral cavity, for example a toothpaste, tooth powder, mouthwash, gargle water, pastilles, tooth lotion or chewing gum . The term “sweetener” means agents that are not themselves oral genome (I)

Menus are either kept for digestion or in the mouth, but should instead be added to other digestible products or oral agents to make them sweet or to increase their sweetness.

Although sucrose is still the most commonly used sweetener, many attempts have been made to find substantially sweeter alternatives that could be used if desired, a high level of low calorie sweetness and / or "inem" low risk of dental caries, for example for dietary products or in the production of soft drinks. The two most successful non-sucrose-based sweeteners (i.e., sweeteners that contain a substance other than sucrose) have been saccharin and cyclamate, each having about 200 and about 30 times the sweetening power of sucrose. However, the use of these sweeteners, especially cyclamate, has recently been restricted or banned in some countries due to doubts about their safety. Saccharin also has the disadvantage of an unpleasantly bitter aftertaste that can be noticed by many people.

Recently, many more non-Saccharo 40s sweeteners have been investigated, some of which are natural and others synthetic, with a wide range of chemical structures detected. These compounds have proteins such as monellin, thaumatin and miraculin; Dipeptides such as aspartan; and dihydrochalcones such as Neohesperi-45 dindihydrochalcon. However, apart from that

Difficulties in synthesizing or extracting such sweeteners do not necessarily have the same sweet quality as sucrose. In particular, compared to sucrose, the sweetness can start relatively slowly and relatively persist, whereby there may be a licorice-like or other aftertaste which makes the sweetener unsuitable as a direct substitute for sucrose if these differences cannot be masked.

Although numerous sweeteners with very different chemical structures have now been investigated, it is important to note that a sweetness that exceeds that of sucrose has not been found in any sucrose derivative or in any other carbohydrate: where an intensely sweet substance has been discovered, 60 such as saccharin, cyclamate and the other non-sucrose-based sweeteners that have already been mentioned, their structure has always been very different from that of sucrose. In fact, it is known that the presence of some substituents on the sucrose molecule can destroy the sweetness and even give it a bitter taste.

It is therefore extremely surprising and in complete contrast to the previous state of knowledge about sweeteners based on non-sucrose that it has now been determined

3rd

624 835

that certain derivatives of sucrose and a sucrose isomer are much sweeter than sucrose itself, the sweetness of which is comparable in intensity to that of saccharin, and of a quality comparable to that of sucrose.

The invention thus relates to a method for sweetening substances, which is defined in claim 1.

The compounds of formula I are not absorbed by the living organism, i.e. are not digested and therefore do not act as food.

The compounds of the formula (I) can be used as sweeteners in any conventional manner, including the sweetening of "digestible products" (as defined above), for example foods, beverages and orally administered pharmaceutical preparations and "orally administered agents" ( according to the above definition) for example toothpastes, chewing gums and mouthwashes. They can also be used with conventional liquid or with solid extenders and carriers in «sweeteners» (as defined above).

The extender or carrier comprises any suitable vehicle for the sucrose derivative of formula (I) so that it can be formulated in an agent that can be conveniently used to sweeten other products, such as granules, tablets or in the form of drops. The extender or carrier can thus contain, for example, conventional water-dispersible tabletting ingredients such as starch, lactose and sucrose itself. The extender or carrier may also include low density bulking agents to provide a granular sweetener having a sweetness equivalent to that of sucrose per unit volume, e.g. spray dried maltodextrins, while aqueous solutions may contain adjuvants such as stabilizers, colorants and viscosity adjusters.

Drinks, e.g. Non-alcoholic beverages containing a sucrose derivative of the general formula (I) can be formulated either as sugar-free dietary products or as "reduced sugar" products that contain the minimum amount of sugar required by law. In the absence of sugar, it is desirable to add other substances to create a "mouthfeel" similar to that obtained from sugar, for example 20 pectin or vegetable gum. For example, pectin can be added to a bottle syrup in an amount of 0.1 to 0.15% by weight.

A number of compounds of formula (I) which can be used according to the invention are shown in the following table.

Connection no.

R1

R2

R3

R4

R5

Approximate sweetness (x sucrose) *

1

Cl

OH

H

OH

OH

20th

2nd

OH

H

Cl

OH

OH

5

3rd

Cl

H

Cl

OH

OH

600

4th

Cl

OH

H

OH

Cl

500

5

Cl

H

Cl

OH

Cl

2000

6

OH

H

Cl

Cl

Cl

4th

7

Cl

OH

H

Cl

Cl

100

8th

Cl

H

Cl

Cl

Cl

200

9

Cl

Cl

H

Cl

Cl

100

Sweetness rating

The sweetness is evaluated in aqueous solution by comparison with a 10% by weight aqueous solution of sucrose. The results were obtained from a small test group of people and are therefore not statistically exact, but reflect the approximate order of sweetness.

The compounds in Table 1 are as follows (the systematic nomenclature is given first, followed by a trivial name based on «galactosaccharose» in cases where there is a 4-chloro substituent):

1. 1 'chloro-1' deoxysucrose

2. 4-chloro-4-deoxy- «-D-galactopyranosyl- / 3-D-fructo-furanoside (i.e. 4-chloro-4-deoxygalactosaccharose)

3. 4-chloro-4-deoxy-a-D-galactopyranosyl-1-chloro-deoxy-β-D-fructofuranoside (i.e. 4, l'-dichloro-4,1 '-dideoxygalactosaccharose)

4. 1 ', 6'-dichloro-1', 6'-dideoxysucrose

5. 4-chloro-4-deoxy - «- D-galactopyranosyl-l, 6-dichloro-1,6-dideoxy-β-D-fructofuranoside (i.e. 4,1 ', 6'-tri-

60 chloro-4,1 ', 6' -trideoxygalactosaccharose)

6. 4,6-dichloro-4,6-dideoxy-a-D-galactopyranosyl-6-chloro-6-deoxy- / J-D-fructofuranoside (i.e. 4,6,6'-trichloro-4,6,6'-trideoxygalactosaccharose)

7. 6, l ', 6'-trichloro-6, l', 6'-trideoxysaccharose

65 8. 4,6-dichloro-4,6-dideoxy-aD-galactopyranosyl-1,6-dichloro-1,6-dideoxy- / jD-fructofuranoside (ie 4,6,1''6'-tetrachloro-4 , 6,1 ', 6'-tetradeoxygalacto-sucrose)

624 835

4th

9. 4,6, r, 6'-tetrachloro-4,6, r, 6'-tetradeoxysaccharose

From Table 1 it can be seen that the chlorine substituents in the 4, 1 'and 6' positions are effective to induce sweetness. A combination of the two such substituents is synergistic and generally increases the sweetness by an order of magnitude over the simple additive increase. Thus, for example, an 1'-chlorine substituent itself gives a sweetness of 20 x and a 4/3 chlorine substituent itself gives a sweetness of 4 x. However, a 4, l'-dichlor combination gives a sweetness of 600 x and a 1, 6'-dichlor combination gives a sweetness of 500 x. Similarly, a combination of all three chlorine substituents increases the sweetness by approximately a further order of magnitude, the 4,1 ', 6'-tri-chloro derivative having a sweetness of 2000 x. (All sweets are expressed in multiples of that of sucrose.)

In contrast, a 6-chloro substituent is disadvantageous and causes a reduction in sweetness by antagonizing the action of the other substituents. For this reason, a 6-chlorine substituent R3 in formula (I) can only be present if at least two other chlorine substituents are present.

In general, the 6-chloro substituted compounds are not preferred for this reason - the sweetest compounds contain 4,1'- and 6'-chloro substituents.

The pronounced sweetness of the compounds of the formula (I) is combined with an LD50 (50% lethal dose) value, which in the case of compound 5 in Table 1 is, for example, above 16 g / kg in mice, which is the largest dose which can be administered in practice.

Most of the compounds of formula (I) are known and can be prepared by synthetic routes described in the chemical literature. However, none of the known compounds have previously been recognized to have any useful sweetness.

Compound 5 is in «Carbohyd. Res. », 40, (1975), 285; Compound 6 in «Carbohyd. Res. », 44, (1975) 37 and compound 7 in« Carbohyd. Res. », 25, (1972), 504 and ibid, 44, (1975), 12-13. Compound 2 is in «Carbohyd. Res. », 40, (1975), 285-298.

All compounds of formula (I), both the new and the known ones, can be produced by reacting a sucrose ester containing free hydroxyl groups in the parts to be chlorinated with sulfuryl chloride to obtain the corresponding chlorosulfate derivative. This gives the chlorinated sucrose esters when treated with a chloride ion source such as lithium chloride in an amide solvent such as hexamethyl phosphoric acid triamide. The hydrolysis of the chloroesters, e.g. B. using sodium methoxide in dry methanol, then releases the free chlorosucrose to freedom. The reaction with sulfuryl chloride is conveniently carried out at reduced temperature in an inert solvent in the presence of a base, e.g. Chloroform containing pyridine performed.

A similar methodology can be used for the further chlorination of an already chlorinated sucrose derivative.

In general, the 4-chloro-sucrose derivatives can be obtained by reacting the 4-chloro-galactosucrose analog with a chloride ion source at an elevated temperature, e.g. 100 to 150 ° C, preferably in the presence of a catalytic amount of iodine, can be obtained.

Production methods of compounds of the formula (I) listed in the table above are given below, for example. Percentage concentration data are by weight.

l'-chloro-l'-deoxysaccharose (Compound 1) (a) 1'-chloro-l'-deoxysaccharosehepta acetate

A solution of 2,3,4,6,3 ', 4', 6'-hepta-0-acetylsaccha-

rose (2 g) in a mixture of pyridine (10 ml) and chloroform (30 ml) was treated with sulfuryl chloride (2 ml) at -75 ° C for 45 minutes. The reaction mixture was taken up in ice-cold sulfuric acid (10'e, 200 ml) and dichloromethane (200 ml) and shaken vigorously. The organic layer was then washed successively with water, aqueous sodium bicarbonate and water and then dried (Na2S04). The solution was concentrated and extracted with ether. The insoluble material was filtered off and the filtrate was concentrated to give the corresponding 1 'chlorosulfate derivative (2.1 g).

This syrupy residue (2 g) was then treated with lithium chloride (2 g) in hexamethylphosphoric triamide (HMPA) (10 ml) at 90 ° C for 24 hours. The reaction mixture was poured into ice water and the precipitate formed was collected, washed with water and taken up in ether. The organic layer was dried over sodium sulfate, concentrated, and eluted from a silica gel column with ether / light petroleum (1: 1) to obtain the 1 'chloro-heptaacetate as an amorphous powder. [a] D + 55.0 ° (c 1.2, CHCl3); NMR data: r 4.29 (d, 2 3.5 Hz, H-1); 5.11 (dd, J2.3 10.0 Hz, H-2); 4.56 (t, J3 4 9.5 Hz, H-3); 4.94 (t, J4.5 9.5 Hz, H-4); 4.32 (d, J3.4.4.6Hz, H-3.); 4.60 (t, J4-, 5-6.5 Hz, H-4 '); 7.84-8.01 (7 Ac). Mass spectrum data: f (a) denotes ions attributable to the hexa-pyranosyl cation, and (b) a 3: 1 doublet (1 Cl) attributable to ketofu-ranosyl]: m / e 331a, 307b, 187b , 169a, 145b, 109a.

Analysis for C26H35C10I7.

calculated: C 47.7 'H 5.4 Cl 5.4%

found: C 47.5 H 5.6 Cl 5.7%

(b) l'-chloro-l'-deoxysaccharose A solution of the above intermediate (lg) in dry methanol (10 ml) was treated with a catalytic amount of Im sodium methoxide in methanol at room temperature for 5 hours. A slowly moving product was found by thin layer chromatography (dichloromethane / methanol 3: 1). The solution was deionized by shaking with [Aberlyst] -15 (a polystyrene sulfonic acid resin) in H + form, concentrated and purified by shaking an aqueous solution of the syrup with petroleum ether. The aqueous layer was then concentrated and dried under vacuum to give l'-chloro-l'-deoxysaccharose [ct] D + 57.8 ° (c 0.7, water).

Analysis for C12H21ClO10.

calculated: C 39.9 'H 5.9 Cl 9.8%

found: C 39.7 H 6.1 Cl 9.7%

4,1'-dichloro-4,1 '-dideoxygalactosaccharose (compound 3) (a) 2,3,6-tri-0-acetyl-4-chloro-4-deoxy-aD-galacto-pyranosyl-3,4- di-0-acetyl-6-0-benzene-1-chloro-1-deoxysaccharose A solution of 2,3,6,3 ', 4'-penta-0-acetyl-6'-0-benzoyl-sucrose (2nd g) in a mixture of pyridine (10 ml) and chloroform (30 ml) was treated with sulfuryl chloride (2 ml) at -75 ° C for 45 minutes. The reaction mixture was poured into ice-cold sulfuric acid (10%, 200 ml) while shaking vigorously and then extracted with dichloromethane. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate and water and dried (Na2S04). The solution was concentrated and extracted with ether. The insoluble material was filtered off and the filtrate was concentrated to give the chlorosulfate (2.1 g). This intermediate was then treated with lithium chloride as in Example 1 to obtain the above-mentioned chlorine intermediate.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

624 835

(b) 4-Chloro-4-deoxy-aD-galactopyranosyl-1-chloro-1-deoxy- / 3-D-fructofuranoside A solution of the above-mentioned intermediate from (a) (1 g) in dry methanol was treated with a catalytic Amount Treated in sodium methoxide in methanol at room temperature for 5 hours. A product was obtained by thin layer chromatography (dichloromethane / methanol 4: 1). The reaction was worked up as in Example 1 (b) to give the title compound as a syrup, [a] D + 49.6 ° (c, 0.7, water).

Analysis for C12H20CI2O9:

calculated: C 38.0 H 5.3 Cl 18.7%

found: C 35.7 H 6.0 Cl 20.4%

L ', 6'-dichloro-l', 6'-dideoxysucrose (compound 4) was prepared by a similar methodology: [a] D + 67 ° (c 1.0, methanol)

Analysis for Q2H20CI2O9:

calculated: C 38.0 H 5.3 Cl 18.7%

found: C 37.7 H 5.2 Cl 17.1%

Hexaacetate - white solid foam [a] D + 51.7 ° (c 1.0, CHCI3), mass spectrometry: m / e 331 and 283 (2 Cl). Characterized by reductive dehalogenation with Raney-Nik-kel, H2 and KOH to l ', 6'-dideoxysaccharose hexaacetate - a thick colorless syrup; a] D + = 25.5 ° (c 1.0, CHC13). 100 Hz NMR (C6D6r values) - H-1. 4.36 d (J1> 2 3.5 Hz); H-2. 4.99 q (J2i3 10.5 Hz); H-3.4, 4.17 t (J3.4 10.0 Hz); H-4, 4711 (J4) 5 10.0 Hz); H-1 ', 8.58 s; H-6 ', 8.60 d.

1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4,6-dichloro-4,6-dideoxy-a-D-galactopyranoside (compound 8)

A solution of 6, 1 ', 6'-trichlor-6, 1', 6'-trideoxysaccha-rose (3 g) in pyridine (70 ml) was treated with sulfuryl chloride (35 ml) in dry chloroform (100 ml) at - Treated at 75 ° C for 3 hours. The solution was stirred at 0 to -5 ° C for 2 hours and then at room temperature for 24 hours. The reaction mixture was then diluted with dichloromethane (100 ml) and washed successively with ice-cold sulfuric acid (10%, 250 ml), water, aqueous sodium hydrogen carbonate and water. The organic layer was dried over sodium sulfate and concentrated to give a syrup. The syrupy residue was dissolved in methanol (100 ml) and dechlorosulfated using excess barium carbonate and a catalytic amount of sodium iodide. The inorganic residue was filtered off and the filtrate was concentrated to a syrup. Thin layer chromatography (chloroform / methanol 4: 1) gave 4,6, l ', 6'-tetrachlor-4,6, l', 6'-tetradeoxy-galactosac-charose as the main product. A fast moving, small amount product, possibly a pen tachlor derivative, has also been identified. Purification on a silica gel column using chloroform / acetone (5: 1) gave the tetrachloro derivative in 90% yield.

Exactly equivalent results were obtained by repeating the above methodology, but starting from l ', 6'-di-chloro-l', 6'-dideoxysaccharose or l'-chloro-l'-deoxysaccha-rose instead of 6, r, 6 ' -Trichlor-6, r, 6'-trideoxysaccharose obtained.

[a] D 4-89 ° (c 1.0, methanol). Mass spectroscopy: m / e 199 (2-C1).

Tetraacetate - white solid foam, [a] D + 98.5 ° (c 1.0, CHCI3), 100 MHz, NMR (CDCl3, r values) - 4.28 d (Hl), 5.25 q (H -4), 4.30 d (H-3 '), 4.55 t (H-4') J1i2 3.5 Hz; J3.4 3.0 Hz; J4i5 1.5 Hz; J3.-4. 6.5 Hz; J4-i5. 6.5 Hz; Mass spectrometry: m / e 283 (2 Cl).

Tetramesylate - very pale yellow crystals from dichloromethane / ethanol; Melting point 120-121 °; [a] D + 65.5 ° (c 1.0, CHCI3). 100 MHz NMR (CDC13, r values) H-l 4.18 d

(J12 3.5 Hz); H-2 5.06 q (J2i3 10 Hz); H-3 4.77 q (H3.4 3.5 Hz); H-4 5.20 q (J4.51.5 Hz); H-3 '4.39 d (J3, 4.7', 0 Hz); H-4 '4.65 t (J4.5, 7.0 Hz; mass spectrometry: m / e 355 (2 Cl).

5

4,6, l ', 6'-tetrachlorosucrose (Compound 9) To a solution of 4,6,6'-trichloro-4,6,6'-trideoxy-2,3,3', 4'-tetra-0 -acetylgalactosaccharose 1'-O-monomesity lens sulfonate (1 g) in DMF (15 ml), an excess of Li-10 thium chloride (2 g) and a catalytic amount of iodine (50 mg) were added and the mixture was made up to 140 to Heated at 145 ° C in an oil bath for 18 hours. Thin layer chromatography (benzene / ethyl acetate 3: 1) revealed the absence of a major product that migrated faster than 15% of the starting material. The reaction mixture was cooled, poured into ice-cold water and then extracted with ethyl acetate. The organic extract was washed thoroughly, first with 5% sodium thiosulfate solution and then with water, and then dried. The ethyl-20 tat was evaporated and the residue treated with methanol containing a catalytic amount of sodium methoxide.

The thin-layer chromatogram (chloroform / acetone / methanol / water, 57: 20: 20: 3) now showed the presence of a product that migrated more quickly and was present in smaller quantities and a slow-moving main product - both of which had very similar mobilities , the latter corresponding to 4,6, l'-6, '- tetradeoxy-galactosaccharose (Compound 8) (mixed thin layer chromatogram). 30 The mixture was fractionated over a silica gel column using chloroform / methanol (10: 1) as the eluent. However, a complete separation was not achieved due to the closely adjacent mobility of the two components. The first few fractions contained 35 4,6, l ', 6'-tetrachlor-4,6, l', 6'-tetradeoxy-sucrose, which as a white solid [a] D + 45 ° (c 1.0, MeOH ) was obtained. The structure was confirmed by NMR and mass spectrometry of the following derivatives:

Tetraacetate syrup, [a] D + 30.5 ° (c 1.0 CHC13) NMR 40 (C6D6, r values) - H-l, 4.39 d (J1) 3 4.35 Hz); H-2. 5.14 q__ (J2.310 Hz); H-3,4,271 (J3.410 Hz); H-4 6.11 (J4.510 Hz); H-3 ', 4.20 d (J3% 4. 9.6 Hz); H-4,4,621 (J4., V 6.0 Hz).

Tetramesylate - white crystalline compound, melting point 187 ° (dichloromethane / methanol) [a] D + 29.9 ° (c 1.0, 45 acetone).

Example 1 Sweet tablets for drinks etc.

Each tablet contains:

Compound 3 8 mg

50 or compound 5 2 mg together with a dispersible tablet base (approx. 60 mg), which contains sucrose, gum arabic and magnesium stearate, and corresponds in sweetness to about 4.5 g sucrose.

55 _ Example 2

Filled sweetener A filled sweetener that has the same sweetness as an equivalent volume of sucrose (granulated sugar) is produced by mixing the following ingredients and spray drying to a bulk density of 0.2 g / cm3:

Maltodextrin solution with one

Containing dry weight of 222.2 g

65 compound 3 1.7 g

(or compound 5 0.5 g)

The resulting composition has a sweetness equivalent to about 2 kg of sugar.

624 835

6

Example 3

Cola drink containing sugar, with a reduced calorie content Ingredients for the preparation of 100 ml bottle syrup:

Compound 3 80 mg

(or compound 5 20 mg)

Sugar 60 g

Benzoic acid 35 mg

Phosphoric acid (conc.) 1 ml

Cola flavor 1.1 ml

Color ad lib.

Make up to 100 ml with mineral water This syrup can then be added in 25 ml cans to carbonated 225 ml portions of chilled mineral water.

Example 4

Low-calorie carbonated lemonade (sugar-free)

Ingredients for making 100 ml syrup:

Compound 3 100 mg

(or compound 5 19 mg)

Benzoic acid 35 mg

Citric acid (dry weight) 1.67 g

Lemon essence 0.8 g

Filling up to 100 ml in mineral water This syrup can be added in 25 ml cans to 225 ml portions of carbonated chilled mineral water.

Example 5 Toothpaste

% By weight

Dibasic calcium phosphate 50%

5 glycerin 20%

Sodium lauryl sulfate 2.5%

Spearmint oil 2.5%

Tragacanth gum 1.0%

Connection 3 0.03%

io water 23.97%

The ingredients are mixed together to obtain a spearmint-flavored toothpaste of an acceptable sweetness, but free of sugar or saccharin.

Example 6 Chewing Gum

Polyvinyl acetate butyl phthalyl butyl glycolate 20 polyisobutylene microcrystalline wax calcium carbonate flavor aroma compound 3 25 glucose

Parts by weight 20 3 3 2 2 1

0.07 10

The above chewing gum base can be cut into conventional tablets or strips.

s

Claims (5)

624 835 1,6-dideoxy - /? - D-fructofuranoside, 4,6, l ', 6'-tetrachloro-4,6, l', 6'-tetradeoxysaccharose added individually or as a mixture with one another. 1 6'-dichloro-1 ', 6' -dideoxysacch arose, 4-chloro-4-deoxy-a-D-galactopyranosyl-l, 6-dichloro-1,6- dideoxy - /? - D-fructofuranoside, 4,6-dichloro4,6-dideoxy-a-D-galactopyranosyl-6-chloro-6- deoxy- / 3-D-fructofuranoside, 6,1 ', 6'-trichloro-6, l', 6'-trideoxysucrose, 4,6-dichloro-4,6-dideoxy-a -D-galactopyranosyl-1,6-dichloro 1. A process for sweetening substances, characterized in that the substance has at least one compound of the formula 2. The method according to claim 1, characterized in that in the formula IR1 is chlorine. 2nd PATENT CLAIMS 3. The method according to claim 1 or 2, characterized in that the substance as a compound of the formula I 1 '-chloro-1' deoxysaccharose, .3 ~ 4 wherein R1 is hydroxy or chlorine, R2 and R3 are hydroxy and hydrogen, chlorine and hydrogen, or hydrogen and chlorine, the 4-position being in the D configuration, R4 is hydroxy or, if at least two of R1, R2, R3 and R5 are chlorine represent, R4 is hydroxy or chlorine, and R5 is hydroxy or chlorine with the proviso that at least one of R1, R2 and R3 is chlorine, is added as a sweetener. 4. The method according to any one of the preceding claims, characterized in that an additive to improve the mouthfeel is also added to the substance in the form of a liquid. 4-chloro-4-deoxy-a -D-galactopyranosyl-1-chloro-1-deoxy- ß-D -fructofuranoside, 4-chloro-4-deoxy-a-D-galactopyranosyl - /? - D-fructofurano-sid, 5. sweetener for carrying out the method according to claim 1, characterized in that it contains at least one compound of formula I together with a solid or liquid extender or carrier.