Brominated sucrose derivatives, compositions and methods of use

4,1',6'-Tribromo-4,1',6'-trideoxygalactosucrose

4,1',6'-tri-O-methanesulphonylsucrose pentaacetate was prepared according to the method of Hough and Mufti (Carbohydrate Research 29 (1973) 291-296). The pentaacetate (5 g) was dissolved in hexamethylphosphorictriamide (100 ml) and was treated with lithium bromide (5 g) at 90° C. for 10 days. The reaction mixture was worked up by being poured into ice/water and the resulting precipitate was filtered off and dissolved in diethyl ether. The ether solution was then dried over sodium sulphate and concentrated to a solid. This solid material was then reacted with an acetic anhydride-pyridine mixture (5 ml in 50 ml) and the reaction mixture was again evaporated to dryness. The fully acetylated product was then purified by elution through a silica gel column using diethyl ether-light petroleum (1:1). The structure of the resulting 4,1',6'-tribromo-4,1',6'-trideoxygalactosucrose pentaacetate was confirmed by 1 H-nmr and mass spectrometry.

The tribromopentaaceta (1 g) in methanol (10 ml) was treated with sodium methoxide until a pH of 9 was achieved. After 4 hours at room temperature, the reaction mixture was examined by t.l.c. (dichloromethanemethanol 4:1) to reveal a single slow-moving product. The solution was neutralized with Amberlyst 15 (H 30 ) ion-exchange resin, filtered and concentrated to dryness to yield 4,1',6'-tribromo-4,1',6'-trideoxygalactosucrose (0.65 g 88%, [α] D + +75.2° (c, 1.3 acetone).

4,1',6'-Tribromo-4,1',6'-trideoxygalactosucrose

2,3,6,3',4'-penta-O-acetylsucrose was prepared according to the method of McKeown, Serenius and Hayward, (Canadian J. Chem 35 (1957) 28-36). The pentaacetate (27.6 g) and triphenylphosphine (78.6 g 6 molar equivalents) were dissolved in pyridine (300 ml) at room temperature and then the mixture was cooled to 0° C. Carbon tetrabromide (50 g, 3 molar equivalents) was then added with stirring and the mixture became dark. The mixture was then heated at 75° C. for 11/2 hours and then methanol (50 ml was added and the resulting solution was evaporated to a syrup. This syrup was dissolved in dichloromethane (200 ml) and the resulting solution was washed successively with dilute hydrochloric acid, water and aqueous sodium bicarbonate to neutrality. The dichloromethane solution was then dried over anhydrous sodium sulphate and concentrated to dryness and the residue was stirred with diethyl ether (200 ml). A crystalline precipitate of triphenylphosphine oxide was filtered off, the filtrate was concentrated and the product was crystallised from ethanol to give 4,1',6'-tribromo-4,1',6'-trideoxygalactosucrose pentaacetate (18.5 g, 49%). The structure was confirmed by 1 Hnmr:

4.84 (d, J 1 ,2 3.5 Hz, H-1);

5.37 (q, J 2 ,3 10.0 Hz, H-1);

5.19 (q, J 3 ,4 10.0 Hz, H-3);

5.86 (q, J 4 ,5 1.5 Hz, H-4);

4.77 (d, J 3' ,4' 6.0 Hz, H-3');

5.11 (t, J 4' ,5' 6.0 Hz, H-4');

8.3-8.41 (15H, 5-OAc)

Mass spectral data [(a) indicates a 1:2:1 triplet due to hexopyranosyl cation and (b) indicated a 1:1 doublet due to tetopyranosyl cations]:

M/e: τ371/373/375 (a),

351/353 (b),

311/313/315 (a),

291/293 (b),

231/233 (b),

189/191 (b).

4,1',6'-tribromo-4,1',6'-trideoxygalactosucrose pentaacetate (5 g) was dissolved in methanol (50 ml) and treated with 1N sodium methoxide to pH 9. After 4 hours at room temperature, the solution was neutralized with Amberlyst 15 (H + ) resin, filtered and concentrated to dryness to give 4,1',6'-trideoxygalactosucrose as a dry syrup, [α] D 20 +75.2° (c, 1.3, acetone). In later Examples, the compound is referred to as TBS

4-Bromo-1',6'-dichloro-4,1',6'-trideoxygalactosucrose (1)

2,3,6,3',4'-Penta-O-acetyl-1',1',6'-dichloro-1',6'-dideoxysucrose

A solution of 2,3,6,3',4'-penta-O-acetylsucrose (16.6 g) in pyridine (100 ml) was treated with triphenylphosphine (26.2 g, 4 ME) to give a clear solution at room temperature. After cooling to 0° C., carbon tetrachloride (9.2 g, 2 ME) was added and the stirred mixture heated to 70° for 1.5 h. Tlc revealed a major product corresponding to the required compound. Methanol (20 ml) was added to the cooled reaction mixture which was then evaporated. The residue was dissolved in dichloromethane and this was washed with water, 1M hydrchloric acid, saturated aqueous sodium biucarbonate solution and water, then dried, filtered through charcoal and evaporated. The resulting syrup was stirred with ether for 1 h and the crystalline precipitate of triphenylphosphine oxide was filtered off. The filtrate was evaporated and eluted from a silica gel column using ether-petrol (1:1) to give the 1',6'-dibromo derivative (6.6 g, 37%).

(2) Bromination to give 4-bromo-1',6'-dichloro-4,1' ,6'-trideoxygalactosucrose penta-acetate

A solution of the dichloro derivative (6.6 g) in pyridine (70) was treated with triphenylphosphine (8.7 g, 3 ME), then cooled to 0° C. and carbon tetrabromide (5.6 g, 1.5 ME) added. The reaction mixture was heated to 70° for 2 h after which tlc revealed a single product. Methanol (10 ml) was added to the cooled reaction which was then evaporated. The residue was worked up as described in step (1). 4-Bromo-1',6'-dichloro-4,1',6'-trideoxygalactosucrose penta-acetate was obtained by crystallisation from ethanol and recrystallised to give 5.2 g (71%).

(3) De-acetylation

A solution of the penta-acetate (5.2 g) in methanol (50) ml) was treated with 1M sodium methoxide in methanol to pH and at room temperature for 3 h. The solution was neutralised with Amberlyst 15 [H + ] resin, filtered and evaporated to give 3.3 g (95%) of 4-bromo-1',6'-dichloro-4,1',6'-trideoxygalacosucrose as a syrup; [α] D 20 +81.2° (c 1.0, H 2 O).

4-Chloro-1',6'-dibromo 4,1',6'-trideoxygalactosucrose

A mixture of 2,3,6,3',4'-penta-O-acetylsucrose (50 g) and trityl chloride (100 g) (of ca. 75% purity) in pyridine (400 ml) was heated at 80° for 8 hrs. The reaction mixture was poured into water and the water was then decanted away from the precipitate. The water-washed precipitate was then dissolved in dichloromethane which was washed with 1M HCl, and with saturated aqueous sodium bicarbonate and then dried, filtered through charcoal and evaporated. The residue was taken up in methanol, from which tritanol crystallized. The precipitate was filtered off and the filtrate was evaporated. The residue was then dissolved in pyridine 300 ml and stirred with molecular sieves (0.4 nm) for two hours. The sieves were then filtered off and to the pyridine solution was added triphenylphosphine (50 g, 2 ME) followed by carbon tetrachloride (15 ml, 1.5 ME) at room temperature. The mixture was heated to 70° for 11/2 hours and then cooled. Methanol (20 ml) was added and the mixture was evaporated. The residue was dissolved in dichloromethane which was washed with 1M HCl and aqueous sodium bicarbonate and then dried, filtered through charcoal and evaporated. The residue was taken up in ether and the crystalline precipitate of triphenylphosphineoxide was filtered off.

The contents of ether solution were then taken up in glacial acetic acid (750 ml) and heated to about 110°; water (15 ml) was added and the mixture was gently refluxed (about 120°) for 1 hour. It was then evaporated at reduced pressure at under 50° and co-distilled with toluene. Tritanol present in the mixture was crystallized from a methanol solution and the remaining product was then subjected to column chromatography on silica gel using ether as the eluent to give 4-chloro-4-deoxygalactosucrosepentaacetate (6.2 g, 12%).

To a solution of the above pentaacetate (6.2 g, 1 ME) and triphenylphosphine (11.4 g, 4 ME) in pyridine (100 ml) was added, at room temperature, carbon tetrabromide, (7.3 g, 2 ME). This mixture was heated at 80° for 1 hour, cooled and further triphenylphosphine (5.7 g) and carbon tetrabromide (3.7 g) were added to the reaction mixture which was then heated at 80° for a further 1 hour to complete the reaction. The mixture was cooled and methanol (20 ml) was added. The mixture was then evaporated to give a residue which was dissolved in dichloromethane. The solution was washed with 1 HCl and aqueous sodium bicarbonate and then dried, filtered through charcoal and evaporated. The residue was taken up in ether, from which a crystalline precipitate of triphenylphosphine oxide was filtered off. The filtrate was evaporated and residue was dissolved in ethanol which then yielded 5.9 grams (80%) of the 4-chloro-1',6'-dibromo derivative as the pentaacetate in the form of crystals. Recrystallization from ethanol gave 5.1 g of purified pentaacetate.

This material (1.5 g) was deacetylated using sodium methoxide in methanol at pH approximately 9.5 room temperature. The solution was neutralized with Amberlyst 15 H + resin and then filtered and evaporated to give 4-chloro-1',6'-dibromo-4,1',6'-trideoxygalacosucrose (1.0 g, 95%) [α] D 20 +52.3° (c=0.7, H 2 O) Melting point 87°-93° (Decomp.).

1',6'-Dibromo 1',6'-dideoxygalactosucrose

2,3,6,3',4'-Penta-O-acetyl sucrose (13.8 g) was dibrominated in a manner analogous to that of Example 4 using 26.4 g (4 ME) of triphenyl phosphine and about 16.6 g, (2 ME) of carbon tetrabromide in pyridine (100 ml) at 70°. The progress of the reaction was followed by t.l.c. and the product isolated and purified as in Example 4 to yield 6.7 g (40%) of the pentaacetate which was deacetylated as before to give 4.1 g of the product, recrystallised from ethanol/ethyl acetate/ether to give 2.8 g (41%). [α] D 20 +71.1° (c=0.4, H 2 O).

Sweetening tablets for beverages

Each tablet contains TBS 5 mg, together with a dispersible tablet base (ca. 60 mg) containing sucrose, gum arabic and magnesium stearate, and is equivalent in sweetness to about 4.5 g sucrose.

Bulked Sweetener

A bulked sweetener having the same sweetness as an equivalent volume of sucrose (granulated sugar) is prepared by mixing the following ingredients and spray-drying to a bulk density of 0.2 g/cc:

Maltodextrin solution containing

dry weight: 222.2 g

TBS: 1.25 g

The resulting composition has a sweetening power equivalent to approximately 2 kilograms of sugar.

Reduced calorie cola drink containing sugar

Ingredients to prepare 100 ml bottling syrup:

TBS: 50 mg

Sugar: 60 g

Benzoic acid: 35 mg

Phosphoric acid (con.): 1 ml

Cola flavour: 1.1 ml

Colour: ad lib

Make up to 100 ml with mineral water.

This syrup may then be added in 25 ml doses to 225 ml aliquots of carbonated chilled mineral water.

Carbonated low calorie lemonade (sugar free)

Ingredients to prepare 100 ml syrup:

TBS: 65 mg

Benzoic acid: 35 mg

Citric acid (dry base): 1.67 g

Lemon essence: 0.8 g

Make up to 100 ml in mineral water.

This syrup can be added in 25 ml doses to 225 ml aliquots of carbonated chilled mineral water.

Toothpaste

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% by weight

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Dibasic calcium phosphate

50%

Glycerol 20%

Sodium lauryl sulphate

2.5%

Spearmint oil 2.5%

Gum tragacanth 1.0%

TBS 0.02%

Water 23.97%

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The ingredients are mixed to produce a spearmint flavoured toothpaste of acceptable sweetness but free from sugar or saccharin.

Chewing gum

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parts by

weight

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Polyvinyl acetate 20

Butyl phthalylbutylglycolate

3

Polyisobutylene 3

Microcrystalline wax

2

Calcium carbonate 2

Flavouring/aroma 1

TBS 0.045

Glucose 10

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