NO142283B - SOETNINGSMIDDEL. - Google Patents

Description

The present invention relates to a sweetener

for "swallowable products" and "oral cavity products".

A "swallowable product" means a product which, in normal use, is intended to be swallowed, e.g. a food or beverage, or an orally administered pharmaceutical substance. By "oral cavity product" is meant a product which, in use, is not intended to be swallowed as such, but which is taken in the mouth for the treatment of the throat or cheek cavity, e.g. toothpaste, tooth powder, mouthwash, gargle, lozenges, toothpaste or chewing gum. A sweetener means a substance that is not taken orally as such, neither to be swallowed nor to keep

des in the mouth, but instead is intended to be added to other ingestible or buccal products to sweeten them or increase their sweetness.

Important ingestible products are sweetened indulgences in any form, i.e. solid, semi-solid or liquid form, e.g. cake batter, egg cream, ice cream and drinks such as fruit juice, sugar-containing juice and mineral water. Examples of indulgences with high sweetness are hard and soft sweets, candies or drops, fondant, foam sugar sweets, gummy sugar sweets, alcoholic drinks, candies, lozenges, fruit pastes, chewing gum, fizzy powder, marzipan, nougat, chocolate and cocoa products.

Although sucrose is the most widely used sweetener,

many attempts have been made to find significantly sweeter alternatives that could be used when it is desirable to combine a high degree of sweetness with a low calorie content and/or a low risk of caries, e.g. in diet products and in the production of non-alcoholic beverages. The two most successful sweeteners

which are not based on sucrose (i.e. sweeteners containing

holds a different compound than sucrose itself) has until today been saccharin and cyclamate, which respectively have approx. 200 and approx. 30

times the sweetening power of sucrose, but the use of these sweeteners, especially cyclamate, has recently been restricted or banned in some countries due to doubts about their safety. Saccharin has: also the disadvantage that it has a bitter aftertaste that can more-

hated by many people.

In recent times, many other non-sucrose sweeteners, some of natural origin and others synthetic, have been developed which have many different chemical structures. These compounds include proteins such as monellin, thaumatin and miraculin, dipeptides such as aspartame, as well as dihydrochalcones such as neohesperidin dihydrochalcone. However, apart from the difficulties in manufacturing or extracting these sweeteners, they do not necessarily have the same sweetness quality as sucrose. In particular, compared to sucrose, the sweeteners may be slow to take effect and relatively long-lasting, and there may be a licorice-like or other aftertaste that makes the sweetener unsuitable as a direct replacement for sucrose unless these differences can be masked.

Although numerous sweeteners with many different chemical structures have now been developed, it is important to note that sweetness significantly greater than that of sucrose has not yet been observed in any sucrose derivative or in any other carbohydrate. When a very sweet substance has been found, such as saccharin, cyclamate and the other non-sucrose sweeteners mentioned above, its structure has always been very different from sucrose. It is known that the presence of some substituents in the sucrose molecule can actually destroy its sweetness and also cause a bitter taste.

Quite surprisingly and completely contrary to previous knowledge of non-sucrose sweeteners, according to the invention it has been shown that certain derivatives of sucrose and a sucrose isomer are much sweeter than sucrose itself, their sweetness being comparable in intensity to the sweetness of saccharin, but they has a similar quality to sucrose.

The sweetener according to the invention is characterized in that it contains a compound with the general formula:

1 2 3

where R a: a hydroxy group or a chlorine atom, R and R are respectively a hydroxy group and a hydrogen atom, a chlorine atom and a hydrogen atom or a hydrogen atom and a chlorine atom, the 4-position having D configuration, R^ is a hydroxy group, or

1 2 3 5 4

if at least two of R , R , R and R are chlorine atoms, R is a hydroxy group or a chlorine atom, and R <5>is a hydroxy group

12 3

or a chlorine atom, provided that at least one of R , R , and R is a chlorine atom.

The compounds with the formula (I) can be used as sweeteners in the usual way, such as sweetening "swallowable products", e.g. foodstuffs, beverages and orally administered pharmaceutical substances, and of "oral cavity products", e.g. toothpaste, chewing gum and mouthwash. They may contain conventional liquid or solid extenders and carriers.

The extender or carrier comprises any suitable carrier for the sucrose derivative with the general formula (I), so that this can be formulated into a substance that can be suitably used for sweetening other products, e.g. granules, tablets or drops. The extender or the carrier can thus include e.g. conventional water-dispersible, tablet-forming ingredients, such as starch, lactose and sucrose itself, low-density bulking agents to produce a granulated sweetener having the same sweetness per volume unit such as sucrose, e.g. spray-dried maltodextrins, as well as aqueous solutions containing auxiliary substances, such as stabilizers, dyes and viscosity-regulating agents.

Beverages, such as soft drinks, containing a sucrose derivative of the general formula (I) can be formulated either as sugar-free dietetic products or as "reduced sugar" products containing the minimal amount of sugar required by law. In the absence of sugar, it is desirable to add other substances to produce a "mouthfeel" similar to that produced by sugar, e.g. pectin or an edible gum. E.g. pectin can be added in a quantity of from 0.1 to 0.15% in a juice to be bottled.

A number of compounds of the general formula (I) which can be used according to the present invention are indicated in

the table below.

The sweetness is assessed in aqueous solution by comparison with

a 10% by weight aqueous solution of sucrose. The results were obtained with a small taste panel and are therefore not statistically accurate, but indicate the approximate order of magnitude in terms of sweetness.

The connections in table 1 are the following, as the systematic

iscal nomenclature is given first, followed by a trivial name based on "galactosucrose" in those cases where a 4-chloro substituent is present:

1. 1'-chloro-1'-deoxysucrose

2. 4-chloro-4-deoxy-a-D-galactopyranosyl-3-D-fructofuranoside (4-chloro-4-deoxygalactosucrose) 3. 4-chloro-4-deoxy-«-D-galactopyranosyl-1-chloro-l- deoxy-3-D-fructofuranoside (4,1'-dichloro-4,1'-dideoxygalactosucrose)

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

5. 3-chloro-4-deoxy-α-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-B-D-fructofuranoside (4,1', 6 '-trichloro-4,1', 6 '- trideoxygalactosucrose) 6. 4,6-dichloro-4,6-dideoxy-ct-D-galactopyranosyl-6-chloro-6-deoxy-B-D-fructofuranoside (4,6,6'-trichloro-4,6,6'-tri- deoxygalactosucrose)

7 . 6,11,6'-trichloro-6,1',61-trideoxysucrose

8. 4,6-dichloro-4,6-dideoxy-α-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-B-D-fructofuranoside (4,6,1',6'-tetrachloro-4,6, 1',6-tetradeoxygalactosucrose)

9. 4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxysucrose

Table 1 shows that chlorine substituents in the 4,1' and 6' positions effectively cause sweetness. A combination of two such substituents is synergistic and generally increases the sweetness approx. 1 order of magnitude instead of being merely additive. Thus gives e.g. a 1'-chloro substituent a sweetness of 20x and a 4B-chloro substituent a sweetness of 4x. But a 4,1'-dichloro combination gives a sweetness of 600x, and a 1',6'-dichloro combination gives a sweetness of 500x. Correspondingly, a combination of all three chlorine substituents increases the sweetness by a further approximately 1 order of magnitude, the 4,1',6'-trichloro derivative having a sweetness of 2000x (all sweetnesses expressed as a multiple of the sweetness of sucrose).

In contrast, a 6-chloro substituent is disadvantageous and causes a reduction in sweetness by counteracting the effect of the other substituents. For this reason, a 6-chloro substituent, R 3 in formula (I), can only be present when at least two other chlorine substituents are present.

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

The remarkable sweetness of the compounds of formula (I) is combined with an LD5q (lethal dose 50%) which in the case of compound 5 in Table 1 e.g. is over 16 g/kg in mice, which is the largest dose that can be administered in practice.

Most of the compounds of formula (I) are known and

can be produced synthetically as described in chemical literature. But it has not previously been proven that any of the known for-

bonds have usable sweetness.

Thus compound 5 is reported in Carbohyd. Res., 40, (L975),285, compound 6 in Carbohyd. Res., 4-4, (1975), 37 and for compound 7 in Carbohyd. Res., 2J5, (1972), 504 and ibid 4_4,

(1975), 12-13. Compounds reported in Carbohyd. Res., 40,

(1975),' 285-298.

All the compounds with the general formula (I), both new and old, can be prepared by reaction between a sucrose ester which has free hydroxy groups in quantities necessary for them to be chlorinated, and sulph uryl chloride, to form the corresponding chlorosulphate derivative. This on treatment with a source of chloride ions, such as lithium chloride, in an amide solvent, such as hexamethylphosphoric triamide, gives the chlorinated sucrose ester. Hydrolysis of the chloroester, e.g. using sodium methoxide in dry methanol then liberates the free chlorosucrose. The reaction with sulfuryl chloride is preferably carried out at a lower temperature in an inert solvent in the presence of a base, e.g.

in chloroform containing pyridine.

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

In general, 4-chlorosucrose derivatives can be prepared by reaction of the 4-chloro-galactosucrose analogue with a source of chloride ions at a higher temperature, e.g. 100-150°C, preferably in the presence of a catalytic amount of iodine.

The invention will subsequently be explained in more detail by means of examples.

Example 1

1'-chloro-1'-deoxysucrose (compound 1)

a) 1' zk^or^l/-d^oks^sukr^s^h^p^a^c^tat

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

in a mixture of 10 ml of pyridine and 30 ml of chloroform was treated with 2 ml of sulfuryl chloride at -75°C for 45 minutes. The reaction mixture was taken up in 200 ml of ice-cold 10 percent sulfuric acid in 200 ml of dichloromethane and shaken vigorously. The organic layer was then successively washed with water, aqueous sodium bicarbonate and water, and then dried with Na 2 SO 4 . The solution was concentrated and then extracted with ether. The insoluble material was filtered off and the filtrate concentrated, whereby 2.1 g of the corresponding 1<1->chlorosulphate derivative was obtained.

2 g of this viscous residue was then treated with

2 g of lithium chloride in 10 ml of hexamethylphosphoric triamide (HMPA) at 90°C for 24 hours. The reaction mixture was poured into ice water, and the precipitate that formed was washed with water and taken up in ether. The organic layer was dried over sodium sulphate, concentrated and eluted from a silica gel column with ether-light petrol 1:1, whereby the 1'-chloroheptaacetate was obtained as an amorphous powder.

[ct]D + 55.0° (c 1.2, CHCl 3 ); nmr data: x 4.29 (d J1 2 3.5Hz, H-1); 5.11 (dd, J2 3 10.0Hz, H-2); 4.56 (t, J3 4 9.5Hz, H-3); 4.94 (t, J4 9.5Hz, H-4); 4.32 (d, J3, 4.6.5Hz, H-3'); 4.60

(t, J4, 5.6.5Hz, H-4'); 7.84-8.01 (7 Ac). Mass spectral data:

[(a) indicates ions due to hexapyranosyl cation and (b)

a 3:1-doublet (ICI) due to ketofuranosyl :

w/e 331 a, 307 b, 187 b, 169 a, 145 b, 109 a.

Analysis for C26H35Cl017: Calculated: C:47.7; H:5.4r Cl:5.4%

Found : C:47.5; H;5,6:Cl:5,7%

b) 1^-chloro-1_|_-deoxysucrose

1 g of a solution of the above intermediate in 10 ml dry

methanol was treated with a catalytic amount of 1 m sodium methoxide in methanol at room temperature for 5 hours. Thin layer chromatography (dichloromethane-methanol, 3:1) showed a slow moving product. The solution was deionized by shaking with "Amberlyst-15" (a polystyrene sulfonic acid resin) in H+<-> form, concentrated and purified by shaking an aqueous solution of the viscous liquid with gasoline. The aqueous layer was then concentrated and dried under vacuum to give 1'-chloro-1'-deoxysucrose, [α]D + 57.8° (c 0.7, water).

Analysis for c12<H>21<C>1O10: Calculated: C:39.9; H: 5.9; Cl:9.8%

Found : C:39.7; H: 6.1; Cl: 9.7%.

Example 2

4, 1'- dichloro- 4, 1'- dideoxygalactosucrose (compound 3)

a) 2i3i6-tri-O2acetyl-4-chloro-4=deox

A solution of 2 g of 2,3,6,3',4'-penta-O-acetyl-6'-O-benzoyl-sucrose in a mixture of 10 ml of pyridine and 30 ml of chloroform was treated with 2 ml of sulfuryl chloride at - 7 5°C for 4 5 minutes. The reaction mixture was poured into 200 ml of ice-cold 10 percent sulfuric acid with vigorous shaking and then extracted with dichloromethane. The organic layer was washed successively with water, aqueous sodium bicarbonate and water and dried with Na 2 SO 4 . The solution was concentrated and extracted with ether. Insoluble material was filtered off and the filtrate concentrated, whereby 2.1 was obtained

g of the chlorine sulfate. This intermediate was then treated with lithium chloride as in example 1, whereby the desired chlorine intermediate was obtained. b) 4-chloro-4-deoxyY;a-D-2alactogY ra2°SYl~l~!si2 rlil^ eo' csY~^l2l ^Eii3St2fHE5S2§i^ •

A solution of 1 g of the intermediate from a) in dry methanol was treated with a catalytic amount of 1 m sodium methoxide in methanol at room temperature for 5 hours. Thin layer chromatography (dichloromethane-methanol, 4:1) showed one product. This was worked up as in Example lb), giving the desired product as a viscous liquid, [ot] Q + 49.6° (c 0.7, water).

Analysis for <C>12H2()C1209: Calculated: C:38.0; H: 5.3; Cl: 18.7%

Found : C:35.7; H: 6.0; Cl: 20.4%.

By a similar procedure, 1',6'-dichloro-1',6'-dideoxysucrose (compound 4) was prepared: [ct]D + 67° (c 1.0, methanol).

Analysis for c12<H>20C12°9: Bere<3net: C:38.0; H: 5.3; Cl: 18.7%

Found : C:37.7; H: 5.2; Cl: 17.1%.

Hexaacetate: white, solid foam, [αJD + 51.7° (c 1.0, CHCl^). Mass spectrometry m/e 331 and 283 (2 Cl). Characterized by reductive dehalogenation with Raney nickel, H2 and KOH to 1',6'-dideoxysucrose hexaacetate, a colorless viscous liquid,

[cOD + 25.5° (c 1.0, CHCl 3 ).

100 Hz nmr (C,D, T values) - H-l, 4.36 d (J, _ 3.5 Hz): H-2,

bb ± , z

4.99 q (J2 3 10.5 Hz): H-3, 4.17 h (J3 4 10.0 Hz): H-4, 4.71 h (J4 5 10.0 Hz): H-l ', 8.58 s: H-6<*>, 8.60 d. ; Example 3 ; 1, 6- dichloro- 1, 6- dideoxy- S- D- fructofuranosyl- 4, 6- dichloro-4, 6 - dideoxy-g-D-galactopyranoside (compound 8). ;A solution of 3 g of 6,1',6'-trichloro-6,1<1>,6'-trideoxysucrose in 70 ml of pyridine was treated with 35 ml of sulfuryl chloride in 100 ml of dry chloroform at -7 5°C for 3 hours. The solution was stirred at between 0 and -5°C for 2 hours and then at room temperature for 24 hours. The reaction mixture was then diluted with 100 ml of dichloromethane and washed successively with 250 ml of ice-cold 10 per cent sulfuric acid, water, aqueous sodium bicarbonate and water. The organic layer was dried over sodium sulfate and concentrated to give a viscous liquid. The viscous residue was dissolved in 100 ml of methanol and dechlorosulphated using excess barium carbonate and a catalytic amount of sodium iodide. The inorganic residue was filtered off and the filtrate concentrated to a viscous liquid. Thin layer chromatography (chloroform-methanol, 4:1) showed 4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxygalactosucrose as the main product. A minor, rapidly moving product, probably a pentachloro derivative, was also observed. Purification in a column of silica gel using chloroform-acetone (5:1) gave the tetrachloro derivative in 90% yield. ;Exactly the same results were obtained when the above procedure was repeated, but starting from 1',6'-dichloro-1',6'-dideoxy-sucrose or 1'-chloro-1'-deoxysucrose instead of 6,1',6' -trichloro-6,1',6'-trideoxysucrose. ;[a] + 39° (c 1.0, methanol). Mass spectroscopy: m/e 199 (2-C1). ;Tetraacetate: white solid foam, [ ajD + 98.5° (c 1.0, CHCl 3 ), 100 MHz nmr (CDC 13 , T values) - 4.28 d (H-l), 5.25 q (H- 4), 4.30 d(H-3'), 4.55 h (H-4')J1 2 3.5 Hz: J3 4 3.0 Hz: 5 1.5 Hz: J3, 4, 6, 5 Hz: J4 , , 6.5 Hz. Mass spectrometry: m/e 283 (2 Cl). ;Tetramesylate: very pale yellow crystals from dichloromethane-ethanol, m.p. 120-121°C: [αjD + 65.5° (c 1.0 CHCl 3 ). 100 MHz nmr (CDC13, T values) H-l 4.18 d { J1 2 3.5 Hz): H-2 5.06 q { J2 3 10 Hz): H-3 4.77 q (J3 4 3, 5 Hz): H-4 5.20 q (J4 5 1.5 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). ;Example 4 ;4, 6, 1', 6'-tetrachlorosucrose (compound 9) ;To a solution of 1 g of 4,6,6'-trichloro-4,6,6 *-trideoxy-2,3,3' ,4'-tetra-O-acetylgalactosucrose-1'-O-monomesitylenesulfonate in 15 ml of dimethylformamide, an excess of lithium chloride (2g) and a catalytic amount of 50mg of iodine were added, and the mixture was heated at 140-145° C in an oil bath for 18 hours. Thin layer chromatography (benzene-ethyl acetate, 3:1) indicated the presence of a major product which moved faster than the starting material. The reaction mixture was cooled, poured into ice-cold water and then extracted with ethyl acetate. The organic extract was washed well, first with 5 percent sodium thiosulphate solution and then with water, and dried. The ethyl acetate was evaporated and the residue was treated with methanol containing a catalytic amount of sodium methoxide.

Thinning's flash chromatograph (chloroform/acetone/methanol/water, 57:20:20:3) now showed the presence of a faster minor product and a slower major product. Both had mobility very similar to that of 4,6,1•,6'-tetradeoxygalactosucrose (compound 8) (mixed thin layer chromatography), and the major product corresponded to this compound. The mixture was fractionated in a column of silica gel using chloroform-methanol (10:1) as eluent. Although complete separation was not achieved due to the two constituents having so

equal mobility, the.-first few f raks contained ions. 4 , 6 ,.1' , 6 '-tetrachloro-4,6,1',6'-tetradeoxysucrose which was obtained as a white solid, [dQ + 45° (c 1.0, MeOH). The structure was confirmed by nmr and mass spectrometry for the following derivatives:

Tetraacetate: viscous liquid, [a]Q + 30.5° (c 1.0

CHC13) nmr, (CgDg t values) -H-l, 4.39 d { J1 2 4.35 Hz): H-2, 5.14 q (J2 3 10Hz): H-3, 4.27 t (J3 4 10 Hz): H-4, 6.1 h (J4.5 10 Hz): H-3', 4.20 d (J3, 4, 9.6 Hz): H-4', 4.62 h (J^, 5, 6.0 Hz) .

Tetramesylate: white, crystalline compound, mp 187°C,.

(dichloromethane-methanol) [a] + 29.9° (c 1.0, acetone).

Example 5

Sweetener<g>tablets for beverages etc.

Each tablet contained:

together with approx. 60 g of a dispersible tablet base which contained sucrose, gum arabic and magnesium stearate, and had the same sweetness as approx. 4.5 g of sucrose.

Example 6

Sweetener in loose mass.

A bulk sweetener having the same sweetness as an equal volume of sucrose (farin) was prepared by mixing the following ingredients and spray drying to a bulk density of 0.2 g/cm 3 :

The resulting substance had the same sweetening strength as about 2 kg of sugar.

Example 7

Sugar-containing cola drink with reduced calorie content. Ingredients for making 100 ml of bottling liquid:

Was dissolved up to 100 ml with mineral water.

This liquid can then be added in doses of 25 ml to 225 ml of cooled mineral water.

Example 8

Carbonated lemon soda with low calorie content (sugar-free). Ingredients for making 100 ml of liquid:

Dissolved up to 100 ml in mineral water.

This liquid can be added in doses of 25 ml to 225 ml carbonated, cooled mineral water.

Example 9

The ingredients were mixed to produce a toothpaste that had a peppermint oil flavor and acceptable sweetness, but was free of sugar or saccharin.

Example 10

This chewing gum can be cut into regular tablets or strips.

Claims (3)

1. Sweetener, characterized in that it contains a compound with the general formula: where R is a hydroxy group or a chlorine atom, 2 3 R and R are respectively a hydroxy group and a hydrogen atom, a chlorine atom and a hydrogen atom or a hydrogen atom and a chlorine atom, the 4-position having the D configuration, R 4 is a hydroxy group, or if at least two of R 1, R 2, 3 5 4 R and R are chlorine atoms, R is a hydroxy group or a chlorine atom, and R^ is a hydroxy group or a chlorine atom, provided 12 3 that at least one of R , R and R is a chlorine atom. 2. Sweetener in accordance with claim 1, characterized in that in the compound with formula (I) the substituent R'*" is a chlorine atom. 3. Sweetener in accordance with claim 1, characterized in that the compound with the formula (I) is 4-chloro-4-deoxy-α-D-galactopyranosyl-1-chloro-1-deoxy-3-D-fructofuranoside, 1',6' -dichloro-1',6<1->dideoxysucrose, 4-chloro-4-deoxy-α-D-galactopyranosyl-1, 6-dichloro-1, 6-dideoxy-g-D-f rukt.of uranoside, 6,1',6' -trichloro-6,1<1>,6'-trideoxysucrose, 4,6-dichloro-4,6-dideoxy-α-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-3-D-fructofuranoside or 4 ,6,1',6'-tetrachloro-4,5,1',6<1->tetradeoxysucrose.