EP1076661A1

EP1076661A1 - Method of preparation of 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose

Info

Publication number: EP1076661A1
Application number: EP99900192A
Authority: EP
Inventors: Rostislav G. Zhbankov; Tamara E. Kolosova; Anatoly P. Kupriyanenko; Vladimir V. Pilipenko; Lubov K. Prikhodchenko
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-05-15
Filing date: 1999-01-04
Publication date: 2001-02-21
Also published as: RU2217435C2; UA58595C2; WO1999060006A1; AU1864899A

Abstract

The invention relates to the method of preparation 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose which can be used as a sugar ingredient (sweetener) of increased sweetness particularly in food and pharmaceutical industries. The most widely used sweetening agent is a natural carbohydrate known as sucrose. In accordance with the invention there is described a method of preparation of 4,1',6'-Trichloro-4,1',6'-trideoxygalactosucrose with sucrose as the base material consisting in selective acetylation of sucrose in pyridine, chlorination of monoacetylated product in Vilsmeier reagent, peracylation of the chloroderivative in pyridine with the deesterification and isolation of the desired product to follow. It has been found that the most preferred conditions for the acetylation stage are the following: the weight of the pyridine excess being 10- times as that of sucrose, conducting the reaction at room temperature and recurring back to the pyridine process with the pyridine removed from the reaction zone by an off-distillation with freezing. The preferred condition for preparation of Vilsmeier reagent is the reaction of phosphorus pentachloride with dimethylformamide (DMF) at the temperature of 0-25 °C in the absence of moisture. Chlorination is preferably conducted at gradual addition of sucrose 6- monoacetate solution in DMF to the prepared solution of Vilsmeier reagent, the temperature being maintained below 20 °C with the following heating of the reaction to 108-110 °C for min. 1,5 hours. Chlorination is conducted for the mixture of products received at the stage of direct acetylation without chromatographic separation of the mixture on ion- exchange resin. Peracylation is conducted by acetic anhydride in pyridine preferably at the temperature of 50 °C for 1,5-2,5 hours. Deacylation is provided by sodium methoxide in alcohol at room temperature for min. four hours at PH 8,8-9,0 with the following neutralization of the reaction by the ion- exchange resin in H-+. The total yield is 60 % at 85 % purity. The advantages of the method filed are provided due the reduction of synthesis stages and simplification of their conducting, considerable increase of the desired (end) product, fast and reliable control of all the stages of technological process by spectral analysis methods.

Description

Method of Preparation 4, 1 ' 6'- Trichloro - 4, 1 ' 6'- Trideoxy galactosucrose .

Field of the Invention

The invention relates to the method of preparation 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose which can be used as a sugar ingredient (sweetener) of increased sweetness particularly in food and pharmaceutical industries. The most widely used sweetening agent is a natural carbohydrate known as sucrose.

Prior Art

As a result of search of alternative sweeteners which, alongside with a high degree of sweetness, would have low energy content, eliminate the risk of obesity and dental caries and could be used for manufacturing of diet food products, the sugar substituties have been found both natural and synthetic ones.

However, such synthtic sweetener as saccharine which is 300 times as sweet as sugar leaves a metallic bitter after- taste. Cyclamate which is 30 times as sweet as sugar hasn't gained widespread usage due to its side- effects. Aspartame is 100- 200 times as sweet as sugar but it is not stable, very sensitive to heat and can't be used in products exposed to thermal processing.

UK patent J\° 1543167 describes chloro- substituted derivatives of sucrose for use in food and pharmaceutical products with 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose in this group having the most considerable degree of sweetness.

The chemical compound described represents crystalline substance of white colour being 400- 800 times as sweet as sucrose and featuring good water solubility high stability and good taste (Food Technology, January 1989, p.60- 63). Its hydrolysis when in human organism is very slow yielding monosaccharide residues, it has no toxic effects, doesn't interact with other food products and has law energy content.

Known is the method of preparation 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose (UK patent N° 2145080 A) consisting in reaction of a fructosyl sugar such as sucrose or raffinose in the presence of fructosyetransferase immobilized on cell ulose derivatives with halogenation of the resulting fructosyl disaccharide to follow. The yield of the desired product is 50% with 85% purity. Industrial utilization of the method described above entails certain difficulties particularly due to complexity of enzyme preparation, necessity to carefully remove the enzyme from the reaction to prevent hydrolysis of 6- acetate sucrose and the complexity of enzyme regeneration. Also known in the art (UK patent JV° 2079749 A) is the method of preparation 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose consisting in: a) reaction of sucrose with acylating reagent under conditions yielding the mixture of acylated sucrose derivatives containing mainly 6- monoacylated product, b) separation of 6- monoacylated sucrose derivatives from other acylated derivatives, c) reaction of 6- monoacylated sucrose with the chlorinating agent capable of providing chlorination in positions 4, 1 ' and 6', d)deacylation and isolation of 4, 1', 6'- trichloro - 4, 1', 6'- trideoxygalactosucrose. The desired product thus prepared is of 99% purity with an overall yield of 5%. Since the abovementioned method doesn't satisfy technological requirements due to low yield of the desired product and the presence of separation stage (stage b) the aim of this invention is working out of the industrial method of preparation 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose which doesn't have the abovementioned disadvantages.

Summary of the Invention

The target aimed has been achieved by the invention filed herein. In accordance with the invention there is described a method of preparation of 4, V, 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose with sucrose as the base material consisting in selective acetylation of sucrose in pyridine, chlorination of monoacetylated product in Vilsmeier reagent, peracylation of the chloroderivative in pyridine with the de- esterification and isolation of the disired product to follow.

It has been found that the most preferred conditions for the acetylation stage are the following: the weight of the pyridine excess being 10- times as that of sucrose, conducting the reaction at room temperature and recurring back to the pyridine process with the pyridine removed from the reaction zone by an off- distillation with freezing.

The preferred condition for preparation of Vilsmeier reagent is the reaction of phosphorus pentachloride with dimethylformamide (DMF) at the temperature of 0- 25 °C in the absence of moisture. Chlorihation is preferably conducted at gradual addition of sucrose 6- monoacetate solution in DMF to the prepared solution of Vilsmeier reagent, the temperature being maintained below 20°C with the following heating of the reaction to 108- 1 10°C for min. 1,5 hours. Chlorination is conducted for the mixture of products received at the stage of direct acetylation without chromatographic separation of the mixture on ion- exchange resin. Peracylation is conducted by acetic anhydride in pyridine preferably at the temperature of50°C for 1,5- 2,5 hours.

Deacylation is provided by sodium methoxide in alcohol at room temperature for min. four hours at PH 8,8- 9,0 with the following neutralization of the reaction by the ion- exchange resin in H-" . The total yield is 60% at 85% purity.

The advantages of the method filed are provided due the reduction of synthesis stages and simplification of their conducting, considerable increase of the desired (end) product, fast and reliable control of all the stages of technological process by spectral analysis methods.

Detaled Description of the Actual Implementations The examples of the actual implementation described below illustrate the method filed without limiting the scope of the invention

EXAMPLE 1

Synthesis of 6 -0 -Ac - sucrose

Sucrose (food sugar) (HOg) is dissolved in pyridine (1100 ml) at boiling for 20 minutes The solution is cooled to room temperature and acetic anhydride added (33 ml) The reaction is maintained at room temperature for 1 hour After an ofF- distillation of pyridine in vacuum (freezing out in a trap) a syrup thus prepared consists of the mixture of nonreacted sucrose, mono- and diacetates of sucrose Nonreacted sucrose is separated by its crystallization from alcoholic solution of acetylation product According to the data of thin - layer chromatography (CHCL, MEOH- 2 1) the content of 6- acetate sucrose in the mixture is 60- 65% 125,5 g of a syrup contain 65 g of 6- 0- Ac- sucrose.

Synthesis of pentaacetate of 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose Preparation of Vilsmeier reagent

Dimethylformamide (DMF) (490 ml) is cooled to 0°C in the reaction vessel Then phosphorus pentachloride (PCL₅) (344 g) is added vigorous stirring with the temperature being maintained below 20°C The reaction is held at 0°C for one hour The crystals of Vilsmeier reagent thus prepeared are filtered out and washed with DMF (2X35 ml) and ether (60 ml) The total yield is 260 g Chlorination of 6- 0 -Ac- sucrose Vilsmeier reagent is diluted with DMF (270 ml)in the reaction vessel equipped with a stirrer, a thermometer, a drying tube and a cooling both The solution is cooled to 0 C. The solution of 6- 0- Ac - sucrose is slowly added to the reaction vessel at the temperature below 20°C. Then the reaction is stirre of methanol- ammoniu^m hydroxide (2:1) at the temperature below 500C The reaction is concentrated in vacuum to yield a thick syrup and acetylated with acetic anhydride (860 ml) in pyridine (860 m¹) at the temperature 500C for 2 hours After addition of ethanol (400 ml) the reaction is concentrated to a syrup and full acetate of chlorination ^product is separated as it is uct is separated as it is described in Example 3 The solution of tetraacetate in methanol (10% solutio") is deacetylated by sodium meth°xide (1M, at PH=9) at the room temperature The solution is neutralized by cation- exchange resin, filtered out, decolourised ^by activated charcoal and evaporated in vacuum u^p to a dry residue. The yield of 4, 1 ', 6'- trichq^»<Dae (3x300 ml) The extract thus produced is concentrated to a syrup and dissolved in ethyl- acetate (300 ml ) The ethyl- acetate solution is washed with water (2x200 ml) and the rinsing water is back extracted with ethyl - acetate (2x150 ml) The combined ethyl- acetate extracts are dried over water- free sodium sulfate, filtered out, processed with activated charcoal and concentrated to a syrup. Deacetylation . Preparation of 4, 1', 6'- trichloro - 4, 1', 6'- trideoxygalactosucrose. A syrup thus prepared is dissolved in methanol (ethanol) (10% solution) IM solution of sodium methoxide in methanol is diluted to PH=9 and the solution is stirred for 4 hours at room temperature Neutralization is performed by ion- exchange resin (FT) to PH=7 The solution is again processed with activated charcoal and concentrated in vacuum up to a dry residue The yield of 4, 1 ', 6'- trichloro - 4, 1', 6'- trideoxygalactosucrose is ~ 40%

EXAMPLE 2

The mixture of sucrose acetylation products containing mainly sucrose 6- acetate after separation of nonreacted sucrose, as is described in Example 1, is chlorinated with Vilsmeier reagent prepared under conditions described in Example 1 A suspended residue without filtering from the reaction is dissolved in dry DMF The suspension cooled to 0°C is added with the solution of 6- 0- Ac- sucrose and the chlorination process as well as the subsequent stages of the end product preparation are conducted under the conditions described in example 1 The yield of 4, 1 ', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose is -50%

EXAMPLE 3

The product of selective sucrose acetylation is chlorinated with Vilsmeier reagent according to the method described in Example 2 Vilsmeier reagent suspension (210 g) in DMF (150 ml) cooled to 0°C is slowly added sucrose 6- acetate solution (the actual content of 6- 0- Ac- sucrose in 44 g) in DMF (140 ml) at the temperature below 20°C The reaction is stirred for 1 minutes at 0°C then slowly heated in an oil both to 110°C and stirred at this temperature for 2,5 hours Heating of the reaction is accompained by isolation of chlorous hydrogen which is removed by passing of dry nitrogen through the reaction or pumping out in vacuum to prevent resinfication of the reaction Then the reaction is cooled to 20°C and neutralized by the addition of methanol- hydroxide ammonium mixture (2 1) keeping the temperature below 50°C The reaction is concentrated to a syrup and acetylated by the addition of pyridine (430 ml) and acetic anhydride (430 ml) at the temperature 50°C for 2 hours Then the reaction is cooled and diluted with 200 ml of ethyl alcohol at the temperature below 60°C .After that the reaction is evaporated to a syrup Full acetate of chlorination product in this case is precipitated with water and carefully rinsed

A solid product is filtered out and dried. The yield is 60 g of pentaacetate 4, 1', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose which is deacetylated according to the method described in Example 2 The yield of 4, 1 ', 6'- trichloro - 4, 1', 6'- trideoxygalactosucrose is 60%

EXAMPLE 4

Chlorination is conducted using the mixture of sucrose selective vacetylation products derived according to the method described in Example 1, without separation of nonreacted sucrose The chlorination process and other stages of end product preparation are conducted according to the methods described in Example 2 The yield of 4, 1', 6'- trichloro - 4, 1', 6'- trideoxygalactosucrose is 48 %

EXAMPLE 5

The product of sucrose selective acetylation (without separation of nonreacted sucrose) is chlorinated with Vilsmeier reagent (the temperature conditions have been changed as compared to the chlorination conditions in Example 3) The solution of acetylation product in DMF (137 g) (actual content of 6- 0- Ac- sucrose is 82 g) is slowly added to the solution of Vilsmeier reagent (400 g) in DMF (300 ml) at the maximum temperature 20°C The reaction is stirred at 0°C for 15 minutes, then it is slowly neated for 1,5 hours to 120- 125°C and maintained at this temperature for 1,5 hours. After cooling at room temperature the reaction is neutralized by the mixture of methanol- ammonium hydroxide (2: 1) at the temperature below 50°C. The reaction is concentrated in vacuum to yield a thick syrup and acetylated with acetic anhydride (860 ml) in pyridine (860 ml) at the temperature 50°C for 2 hours. After addition of ethanol (400 ml) the reaction is concentrated to a syrup and full acetate of chlorination product is separated as it is described in Example 3. The solution of tetraacetate in methanol (10% solution) is deacetylated by sodium methoxide (IM, at PH=9) at the room temperature. The solution is neutralized by cation- exchange resin, filtered out, decolourised by activated charcoal and evaporated in vacuum up to a dry residue. The yield of 4, 1', 6'- trichloro - 4, 1 ', 6'- trideoxygalactosucrose is 30%.

Claims

CLAIMS.

1. A method of preparation 4, 1', 6'- trichloro - 4, 1', 6'- deoxygalactosucrose on the base of sucrose consisting in selective acetylation of sucrose in pyridine, chlorination in positions 4, 1 ', 6' of 6- monoacetylated product by Vilsmeier reagent, peracylation of chloroderivative thus prepared in pyridine with the following de- esterification and separation of the desired product.

2. A method as in claim 1, in which the acetylation stage is conducted at room temperature (18- 20┬░C) with the weight of pyridine excess being 10- times as that of sucrose.

3. A method as in claims 1- 2, in which recurring back to the pyridine process is provided with pyridine removed from the reaction zone by an off- distillation with freezing.

4. A method as in claims 1- 3, in which the mixture of products yielded at the stage of direct acetylation in accordance with claims 1- 3 is directly subjected to chlorination.

5. A method as in claims 1- 4, in which the preparation of Vilsmeier chlorinating reagent is conducted by the reaction of phosphorus penta- chloride with N, N- dimethylformamide (DMF) at the temperature not exceeding 20┬░C.

6. A method as in claims 1- 5, in which the chlorination process is preferably conducted at gradual addition of sucrose 6- monoacetate solution in DMF to Vilsmeier reagent at the temperature below 20┬░C with the following heating of the reaction to 108- 110┬░C for max. two hours and holding at 108- 110┬░C for min. 1,5 hours.

7. A method as in claims 1- 6, in which peracylation is conducted by acetic anhydride in pyridine preferably at the temperature 50┬░C for 1,5- 2,5 hours.

8. The method as in claims 1- 7, in which the isolation of full acetate of 4, 1', 6'- trichloro - 4, 1', 6'- trideaoxygalactosucrose is provided by its precipitation with water.

9. A method as in claims 1- 8, in which deacetylation is provided by sodium methoxide solution in alcohol at room temperature for min. four hours at PH 8,8- 9,0.

10. The method as in claims 1- 9, in which the neutralization of the reaction is provided by the use of ion- exchange resin in H.~ form.