KR20080073879A - Preparation method of sucralose - Google Patents

Abstract

A method for preparing sucralose is provided to perform reactions under mild conditions with inhibiting side reactions, thereby producing highly pure sucralose with high yield. A method for preparing sucralose comprises the steps of: (a) after reacting sucrose represented by a formula(2) with a tritylating agent at a temperature of 40-50 deg.C for 16-20 hours, reacting a reaction product with an acetic acid anhydride to prepare a compound of 6,1',6'-tri-O-tritylsucrosepenta-acetate represented by a formula(3); (b) reacting the compound of the formula(3) with the same equivalent of HCl gas to prepare a compound of 2,3,4,3',4'-penta-O-acetylsucrose represented by a formula(4); (c) isomerizing the compound of the formula(4) under a base catalyst at room temperature for 5-7 hours to prepare a compound of 2,3,6,3',4'-penta-O-acetylsucrose represented by a formula(5); (d) chlorinating the compound of the formula(5) at a temperature of 100-110 deg.C for 3-5 hours to prepare a compound 4,1',6'-trichloro-4,1',6'-trideoxy-2,3,6,3',4'-penta-O-acetyl-galactosucrose represented by a formula(6); and (e) after deacetylating the compound of the formula(6), filtering it with a cation exchange resin to prepare 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose. Further, the tritylating agent is trityl chloride.

Description

Preparation method of sucralose {Preparation method of sucralose}

1 shows ¹ H-NMR spectroscopy (nuclear magnetic resonance spectroscopy) data of 6,1 ′, 6′-tri-O-trityl sucrosepenta-acetate, the product of step 1 of Example 1 of the present invention,

FIG. 2 shows ¹³ C-NMR data of 6,1 ′, 6′-tri-O-trityl sucrosepenta-acetate, the product of Step 1 of Example 1 of the present invention,

FIG. 3 shows infrared spectroscopy (infrared-ray spectroscopy) data of 6,1 ′, 6′-tri-O-trityl sucrosepenta-acetate, the product of Step 1 of Example 1 of the present invention,

Figure 4 shows the ¹ H-NMR data of 2,3,4,3 ', 4'-penta-O-acetyl sucrose which is the product of Step 2 of Example 1 of the present invention,

5 shows ¹³ C-NMR data of 2,3,4,3 ', 4'-penta-O-acetylsucrose, which is the product of Step 2 of Example 1 of the present invention,

6 shows IR data of 2,3,4,3 ', 4'-penta-O-acetyl sucrose, which is the product of Step 2 of Example 1 of the present invention,

7 shows ¹ H-NMR data of 2,3,6,3 ', 4'-penta-O-acetyl sucrose, which is the product of Step 3 of Example 1 of the present invention,

8 shows ¹³ C-NMR data of 2,3,6,3 ', 4'-penta-O-acetylsucrose, which is the product of Step 3 of Example 1 of the present invention,

FIG. 9 shows IR data of 2,3,6,3 ', 4'-penta-O-acetylsucrose, which is the product of Step 3 of Example 1 of the present invention,

10 is 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'- which is the product of step 4 of Example 1 of the present invention; ¹ H-NMR data of penta-O-acetyl-galactosucrose is shown,

11 is 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'- which is the product of step 4 of Example 1 of the present invention. ¹³ C-NMR data of penta-O-acetyl-galactosucrose is shown,

12 is 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'- which is the product of step 4 of Example 1 of the present invention. IR data of penta-O-acetyl-galactosucrose is shown,

FIG. 13 shows ¹ H- of the final product of sucralose (4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose) of Example 1 of the present invention. Represents NMR data,

14 shows ¹³ C-NMR data of sucralose which is the final product of Example 1 of the present invention,

15 shows IR data of sucralose, the final product of Example 1 of the present invention.

The present invention relates to a method for producing sucralose.

Sucralose (4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose), a highly sensitive artificial sweetener, is prepared by regioselective substitution of chlorine atoms in sucrose molecules. do. Sucralose is a white crystalline, non-hygroscopic and free-flowing powder in its pure form. The sucralose has very high solubility in water, ethanol and methanol, and the effect on the pH of the solution is negligibly small.

There have been many reports of conventional methods for preparing sucralose. These all involve the preparation of intermediate sucrose derivatives having a position useful for chlorination while blocking other positions for specific site-selective manufacturing processes.

Fairklu et al. Have reported on the formation of 6,1 ', 6'-tritrityl derivatives of sucrose to overacetylate molecules (Fairclough et al., Carbohydrate Research, 40, (1975) 285-298 ). Thereafter, the 4-acetyl radical obtained is transferred to the 6-position to detritylation to generate 2,3,6,3'4'-penta-O-acetyl sucrose having a deprotected hydroxyl group. Subsequent reaction with the chlorinating agent gives 4,1 ', 6'-trichlorogalacto sucrose penta-acetate, and the removal of the acetyl group produces sucralose. Chlorination advances the dislocation of the array at the 4-position. The 1'- and 6'-positions rotate freely, but the 4-position cannot rotate freely, so the glucose ring is translocated at the 4-position to produce galactose derivatives, the product of which is galactosucrose.

Another method is described in US Pat. No. 4,380,475, wherein the sucrose is reacted with an acylating agent under conditions that can produce a mixture of acylated sucrose derivatives containing the main component 6-mono acylated material (step 1) optionally separating the 6-monoacylated sucrose derivatives from the other acylated derivatives (step 2), wherein the mono acylated sucrose derivatives are chlorinated at the 1 ', 4 and 6'-positions of the sucrose 6-acylate Reacting with a chlorinating agent (step 3) and deacylating and separating the formed sucralose material (step 4).

Furthermore, the sucralose production method described in US Pat. No. 4,362,869 takes several steps to convert sucrose to sucralose. The method tritizes sucrose to protect the three primary alcohol groups (step 1), acetylates the five secondary alcohol groups to acetate (step 2), detritylates the three primary alcohol groups and provides these functional groups Deprotecting (step 3), performing acetyl migration from 4-position to 6-position (step 4), chlorinating the desired alcohol group at 4,1 ', 6'-position (Step 5) and the remaining five alcohol groups are deprotected by deacetylation to produce sucralose (step 6).

In addition to the chlorination method described above, US Pat. No. 4,977,254 as a chlorination method discloses sugars using thionyl chloride together with alkyl quaternary ammonium chlorides to obtain desired chlorodeoxy sugar derivatives in good yields without the production of difficult by-products and An improved method of chlorination of sugar derivatives is described. The alkyl quaternary ammonium salts are used as catalysts to provide precursors of thionyl chloride, chloride ions that promote the substitution of chlorosulfates formed by the reaction of chlorine atoms with intermediate persulfates.

However, in the sucralose synthesis method described in U.S. Patent No. 4,362,869, the reaction product 2,3,4,3 ', 4'-penta-O in the second step is reacted with acetic acid at 0 DEG C in a methylene chloride solvent. -Acetyl sucrose (4-PAS) can be obtained, but purification using amberlite IRC-45 resin in the separation and purification process of this step has the disadvantage that there is no industrial economics because of the high purification cost. . To obtain the reaction product of the third step, the 2,3,4,3 ', 4'-penta-O-acetyl sucrose solution was refluxed under weakly acidic conditions to give 2,3,6,3', 4'-penta-O. Reported that acetyl sucrose (6-PAS) can be obtained, methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK) are solvents for dissolving 2,3,4,3 ', 4'-penta-O-acetyl sucrose. Or toluene was used. However, this is economical because it has to perform the reflux reaction (110 ~ 130 ℃) of the high boiling point solvent. In the fourth step, thionyl chloride or phosphorus pentachloride is reacted with dimethylformamide to form a Vilsmeier type, followed by 2,3,6,3 ', 4'-penta-O-acetyl- sucrose (6 -PAS) to react with 4,1'6'-trichloro-4,1'6'-trideoxy-2,3,6,3 ', 4'-penta-O-acetyl-galactosucrose (TOSPA ), But Vilsmeier chlorinating agent has a black reaction mixture and by-products, making it difficult to use industrially.

In addition, in the process of obtaining the reaction product 6,1 ', 6'-tri-O-trityl sucrose penta-acetate (TRISPA) in U.S. Patent No. 4,801,700, sucrose is chlorinated in the presence of N-methylmorpholine in dimethylformamide. Trityl is reacted at 50 ° C. to obtain a reaction intermediate in which three primary alcohols are tritylated. Dimethylformamide used in this reaction has a high boiling point and is difficult to remove during separation. This method has the disadvantage that the process of concentrating and purifying intermediates is not simple and complex. In the fourth step, 6-PAS and thionyl chloride (SOCl ₂ ) are refluxed in the presence of triphenylphosphine to 4,1'6'-trichloro-4,1'6'-trideoxy-2,3 It has been reported that 6,3 ', 4'-penta-O-acetyl-galactosucrose (TOSPA) is obtained. However, this method produces a triphenylphosphine oxide which is almost the same byproduct of the reaction product, and also has the disadvantage that the byproduct is not completely removed.

Accordingly, the present inventors succeeded in finding a method of performing the reaction under mild conditions while preventing the side reactions occurring in each step of the conventional method of producing sucralose and preparing sucralose. The present invention has been completed.

An object of the present invention is to provide a method for preparing sucralose which is carried out under mild conditions while suppressing side reactions.

In order to achieve the above object, the present invention reacts the sucrose of formula (2) as a starting material with a tritylating agent, and then reacts the reaction product with acetic anhydride (6,1 ', 6'-tri- Preparing O-trityl sucrose penta-acetate (step 1); Reacting the compound of formula 3 prepared in step 1 with an equivalent amount of hydrogen chloride gas to prepare a compound of formula 4 (2,3,4,3 ', 4'-penta-O-acetyl sucrose) (step 2 ); Isomerizing the compound of formula 4 prepared in step 2 under a base catalyst to prepare a compound of formula 5 (2,3,6,3 ', 4'-penta-O-acetyl sucrose) (step 3); The compound of formula 5 prepared in step 3 is chlorinated to give a compound of formula 6 (4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', Preparing 4'-penta-O-acetyl-galactosucrose) (step 4); And deacetylating the compound of Chemical Formula 6 prepared in Step 4, followed by filtration with a cation exchange resin to obtain 4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose. It provides a method for producing sucralose comprising the step of preparing (step 5).

Hereinafter, the method for producing sucralose of the present invention will be described in detail step by step.

Step 1 according to the present invention, as shown in Scheme 2 below, first react the sucrose of formula 2 with a tritylating agent, and then react the reaction product with acetic anhydride 6,1 ', 6'-tri-O -Trityl sucrose penta-acetate (TRISPA, 3) is prepared.

First, the sucrose was heated and stirred with trityl chloride under anhydrous pyridine solvent at 40 to 50 ° C. for 16 to 20 hours to block three primary alcohol groups by replacing with trityl group, and then removing the solvent, and then having the trityl group. 6,1 ', 6'-tri-O-trityl sucrose penta-acetate (3) through a single step reaction in which the reaction product and acetic anhydride are reacted at room temperature for 10 to 14 hours to acetylate the remaining five secondary alcohol groups. Can be prepared.

After the tritylation and acetylation of the reaction product is completed, a precipitate is obtained by adding distilled water and methanol, and then the precipitate is filtered and washed, and then dried, followed by concentration. In step 1, the intermediate compound (3) can be obtained under mild reaction conditions by carrying out the reaction at a low temperature, and the conversion to the product is excellent, so that no intermediate treatment of the intermediate is involved. Furthermore, step 1 uses a single solvent of pyridine, so solvent removal is easy.

In step 2 according to the present invention, 6,1 ', 6'-tri-O-trityl sucrosepenta-acetate prepared in step 1 is reacted with the same amount of hydrogen chloride gas, as shown in Scheme 3 below. , 3,4,3 ', 4'-penta-O-acetyl sucrose (4-PAS, 4) is prepared.

Detritylation of the three primary alcohol groups tritylated in step 1 may deblock these functional groups. After dissolving 6,1 ', 6'-tri-O-trityl sucrosepenta-acetate (3) obtained in step 1 in toluene which is an inert solvent under anhydrous conditions and cooling to 0 ° C, the same amount of hydrogen chloride gas The solution was poured into the solution for 7-9 hours to obtain a precipitate, followed by removal of residual gas. Thereafter, the precipitated 4-PAS slurry was filtered and granulated and reslurried in toluene containing 1% triethylamine, and the precipitate was filtered, washed and dried to give 2,3,4,3 ', 4 '-Penta-O-acetyl sucrose (4) can be easily separated.

In step 2 according to the present invention, since the same amount of hydrogen chloride is used for the compound of Formula 3, the amount of hydrogen chloride can be minimized and the amount of hydrogen chloride remaining in the solution can be minimized.

Step 3 according to the present invention is 2,3 by isomerizing 2,3,4,3 ', 4'-penta-O-acetyl sucrose prepared in step 2 under a base catalyst, as shown in Scheme 4 below. This step is to prepare 6,3 ', 4'-penta-O-acetyl sucrose (6-PAS, 5).

2,3,4,3 ', 4' obtained in step 2 without side reactions under conditions much milder than the method carried out by refluxing of high boiling point solvents (methyl isobutyl ketone, toluene, metel ether ketone, etc.) in the presence of acetic acid The acetyl group in the 4-position of the penta-O-acetyl sucrose 4 can be isomerized by moving it to the 6-position. After using ethyl acetate as a solvent and reacting the base catalyst tert-butylamine with 4-PAS at room temperature for 5-7 hours, adding ethyl acetate in vacuum and heating to remove impurities through thermal filtration, A precipitate is obtained, and the precipitate is filtered and washed and dried to obtain 2,3,6,3 ', 4'-penta-O-acetyl sucrose (5).

At this time, by using a base catalyst such as tert-butylamine, it is possible to suppress deacetylation and to minimize side reactions due to its steric hindrance. As the base catalyst, triethylamine, N-propylamine, di-isopropylamine, morpholine, n-butylamine, isopropylamine, piperidine, diethylamine, etc. can be used as well as tert-butylamine. have.

Step 4 according to the present invention is 4,1 ', 6' by chlorination of 2,3,6,3 ', 4'-penta-O-acetyl sucrose prepared in step 3, as shown in Scheme 5 below Trichloro-4,1 ', 6'-trideoxy-2,3,6,3', 4'-penta-O-acetyl-galactosucrose (TOSPA, 6).

After dissolving 2,3,6,3 ', 4'-penta-O-acetyl sucrose (5) and benzyltriethylammonium chloride obtained in step 3 in toluene, thionyl chloride was added dropwise thereto and then 100-110 ° C. After refluxing for 3 to 5 hours, the mixture was cooled to room temperature and distilled water was added to obtain a precipitate. The precipitate was filtered and washed and dried to obtain 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'-penta-O-acetyl-galactosucrose can be prepared.

The desired alcohol group is chlorinated at the 4,1 ', 6'-position, by using thionyl chloride in combination with alkyl quaternary ammonium chloride, chlorination can be carried out in good yield without the production of by-products.

Step 5 according to the present invention is 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6 prepared in step 4, as shown in Scheme 6 below Deacetylated 3 ', 4'-penta-O-acetyl-galactosucrose and filtered through cation exchange resin to 4,1', 6'-trichloro-4,1 ', 6'-tride Oxygalactosucrose (Sucralose, 1) is prepared.

The remaining five alcohol groups can be deacetylated to produce sucralose. 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'-penta-O-acetyl-galactosucrose obtained in step 4 ( 6) is dissolved in methanol and sodium methoxide solution, and then stirred at room temperature for 1 to 3 hours, followed by addition of cation exchange resin and stirring to neutralize the mixed solution to pH 7 to 7.5. When neutralized, the resin was removed and concentrated until oily, ethyl acetate was added to the concentrate to obtain a precipitate. The precipitate was filtered, washed and dried to give 4,1 ', 6'-trichloro. -4,1 ', 6'-trideoxygalactosucrose (1) can be prepared.

At this time, the cation exchange resin is used Amberlite (Amberite) IRC-50 (H +), Amberlite is a registered trademark.

Hereinafter, the present invention will be described in detail through examples. However, the following examples are only for exemplifying the present invention, and the contents of the present invention are not limited to the following examples.

Example 1 Preparation of Sucralose

Step 1. Tritylation  And Acetylation

Sucrose (100 g) and trityl chloride (270 g) were added to anhydrous pyridine (400 ml) and stirred with heating at 45 ° C. for 18 hours. After pyridine was removed under vacuum, acetic anhydride (600 ml) was added to the obtained syrup product at room temperature, followed by acetylation with stirring for 12 hours. Distilled water (40 ml) was added to the reaction mixture, which was then stirred for 1 hour. Methanol (600 ml) was added and stirred to form a precipitate. The precipitate was filtered, washed with distilled water and methanol and dried to give 6,1 ', 6'-tri-O-trityl water crospenta-acetate (TRISPA, 310 g, 83%).

Results of ¹ H, ¹³ C-NMR and IR spectroscopy analysis of the resulting compound are shown in FIGS. 1 , 2 and 3 .

Step 2. Detritylation

TRISPA (100 g) was dissolved in toluene (400 ml) and the solution was cooled to 0 ° C. Hydrogen chloride gas (2.85 g) was passed through the cooled stirred solution over 8 hours to produce crystals. Thereafter, the precipitated slurry of 2,3,4,3 ', 4'-penta-O-acetyl sucrose (4-PAS) was stirred for 1 hour. The reactor was kept under vacuum for 1 hour to remove residual hydrogen chloride. The mixture was filtered and induce granulation and reslurry for 1 hour in toluene (100 ml) containing 1% triethylamine. The mixture was refiltered, washed with diethyl ether (20 ml) and dried to give 2,3,4,3 ', 4'-penta-O-acetylsucrose (4-PAS, 38 g, 88%).

Results of ¹ H, ¹³ C-NMR and IR spectroscopy analysis of the resulting compound are shown in FIGS. 4 , 5 and 6 .

Step 3. Acetyl Transfer

Ethyl acetate (300 ml) and tert-butylamine (7.5 ml) were added to 4-PAS (200 g), followed by stirring at room temperature for 6 hours. After stirring for 6 hours, the vacuum was maintained for 1 hour. Ethyl acetate (400 ml) was added thereto, the temperature was raised to 75 ° C, hot water filtration to remove insoluble impurities, and the filtrate was crystallized while cooling to room temperature. The reaction was filtered, washed with ethyl acetate and dried to give 2,3,6,3 ', 4'-penta-O-acetyl sucrose (6-PAS, 136 g, 68%).

Results of ¹ H, ¹³ C-NMR and IR spectroscopy analysis of the resulting compound are shown in FIGS. 7 , 8 and 9 .

Step 4. Chlorination

To a slurry in which 6-PAS (80 g, 144.8 mmol) and benzyltriethyl ammonium chloride (10 g, 53.9 mmol) were added to toluene (325 ml), thionyl chloride (42.5 ml, 582.3 mmol) was added at room temperature for 1 hour. It was added dropwise and stirred for 2 hours. The mixture was heated to reflux at 105 ° C for 4 h. The reaction was cooled to room temperature and distilled water (50 ml) was added below 30 ° C. and stirred for 1 hour to form crystals. Thereafter, vacuum was applied for 1 hour to remove gas in the reaction solution. The reaction was filtered, washed once with toluene (125 ml) and once with distilled water (125 ml), then dried to give 4,1'6'-trichloro-4,1'6'-trideoxy-2, 3,6,3 ', 4'-penta-O-acetyl-galactosucrose (TOSPA, 65.1 g, 74%) was obtained.

Results of ¹ H, ¹³ C-NMR and IR spectroscopy analysis of the resulting compound are shown in FIGS. 10 , 11 and 12 .

Step 5. Deacetylation

TOSPA (50 g) was added to methanol (125 ml) / sodium methoxide (0.5 g) solution and stirred at room temperature for 2 hours. TOSPA dissolved within 10 minutes. After 2 hours, Amberlite IRC 50 (H +) resin (7.5 g) was added to the reaction solution, followed by stirring to neutralize the pH to 7-7.5. The resin was removed by filtration and washed with methanol (20 ml). The filtrate was then stirred with activated carbon (4 g) for 30 minutes and filtered again. The filtrate is concentrated under vacuum until it is oily, and ethyl acetate (200 ml) is added to the oily reactant and stirred for 24 hours to crystallize the sucralose. The crystallized sucralose was filtered, washed with ethyl acetate (20 ml) and then dried under vacuum at 40 ° C. for 12 hours to obtain sucralose (30.4 g, 93%).

Results of ¹ H, ¹³ C-NMR and IR spectroscopy analysis of the resulting compound are shown in FIGS. 13 , 14 and 15 .

As described above, according to the present invention, the method of the present invention provides a most efficient and rational method capable of suppressing side reactions generated in the conventional sucralose production process and at the same time performing the reaction under mild conditions. By using this, it is possible to manufacture high yield and high purity sucralose.

Claims (9)

As shown in Scheme 1 below, After reacting the sucrose of Formula 2, which is a starting material, with a tritylating agent, the reaction product is reacted with acetic anhydride to obtain a compound of Formula 3 (6,1 ', 6'-tri-O-trityl sucrose penta-acetate). Manufacturing step (step 1); Reacting the compound of formula 3 prepared in step 1 with the same amount of hydrogen chloride gas to prepare a compound of formula 4 (2,3,4,3 ', 4'-penta-O-acetyl sucrose) (step 2 ); Isomerizing the compound of formula 4 prepared in step 2 under a base catalyst to prepare a compound of formula 5 (2,3,6,3 ', 4'-penta-O-acetyl sucrose) (step 3); The compound of formula 5 prepared in step 3 is chlorinated to give a compound of formula 6 (4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', Preparing 4'-penta-O-acetyl-galactosucrose) (step 4); And After deacetylation of the compound of Formula 6 prepared in step 4, the resultant was filtered with a cation exchange resin to prepare 4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose. Method of producing sucralose comprising the step (step 5). Scheme 1

The method according to claim 1, wherein the tritylating agent is trityl chloride. The method of claim 1, wherein the reaction of the sucrose and the tritylating agent of step 1 is heated and stirred at 40 to 50 ℃ for 16 to 20 hours. The method of claim 1, wherein the reaction product of step 1 and the reaction of acetic anhydride are stirred for 10-14 hours at room temperature. The method of claim 1, wherein the hydrogen chloride gas of step 2 is performed by passing the stirred solution through a stirred solution at 0-2 [deg.] C. for 7-9 hours. The method of claim 1, wherein the reaction of Step 3 is carried out for 5-7 hours at room temperature. The method of claim 1, wherein the base catalyst of step 3 is tert-butylamine, triethylamine, N-propylamine, di-isopropylamine, morpholine, n-butylamine, isopropylamine, piperidine and The method for producing sucralose, characterized in that any one selected from the group consisting of diethylamine. The method of claim 1, wherein the chlorination of step 4 is a method for producing sucralose, characterized in that reflux for 3 to 5 hours at 100 ~ 110 ℃. The method of claim 1, wherein the deacetylation of step 5 is performed by stirring for 1 to 3 hours in a solution of methoxy sodium / methanol at room temperature.

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