HK1138624A - Process for the preparation of sucralose by the chlorination of sugar with triphosgene (btc) - Google Patents

Description

Method for preparing sucralose by using triphosgene (BTC) to chlorinate sucrose

[ RELATED APPLICATIONS ] FOR PREVENTING THE PERFORMANCE OF

This application claims priority from U.S. patent application No. 11/552,789 filed on 25/10/2006. The disclosure of this U.S. patent application is hereby incorporated by reference in its entirety.

[ technical field ] A method for producing a semiconductor device

The present invention relates to a process for the manufacture of sucralose.

[ technical background ] A method for producing a semiconductor device

The monoester method (monoester method) has been used for the synthesis of sucralose. Sucrose is first converted to sucrose-6-ester, which is then chlorinated to obtain sucralose. Sucralose is prepared by alcoholysis of sucralose-6-ester with sodium methoxide/methanol or sodium ethoxide/ethanol. The chlorinating agent which is more commonly used is Vilsmeieregen (Vilsmeieregen), which is generally prepared by reacting DMF with phosgene or thionyl chloride. One major disadvantage of this process is that the amount of sulphur dioxide emitted during chlorination requires an increased number of sulphur dioxide treatment steps and increases the requirements on the equipment. In addition, phosgene is a highly toxic gas and is not suitable for storage, transport and use.

There is therefore a need in the art for an improved method for producing sucralose with high yield and low toxic by-products.

Brief introduction to the invention

One embodiment of the present invention provides a process for preparing sucralose from a sucrose-6-ester, the process comprising forming Vilsmeier reagent from BTC, wherein the Vilsmeier reagent is formed by dissolving BTC in DMF, wherein the molar equivalent ratio of BTC to sucrose-6-ester is in the range of about 2.8: 1 to 3.5: 1.

[ detailed description ] embodiments

The following description of the invention is intended to illustrate various embodiments of the invention. Accordingly, specific modifications of the technical solutions discussed below should not be construed as limiting the scope of the present invention. Various equivalents, changes, and modifications which do not depart from the scope of the present invention will become apparent to those skilled in the art, and it is understood that such equivalent embodiments are to be included within the scope of the present invention.

One embodiment of the present invention provides a process for chlorinating sugars to produce chlorodeoxyderivatives, and in particular a process for chlorinating sugars and sugar derivatives to produce chlorodeoxysugar sweeteners such as sucralose (4, 1 ', 6' -trichloro-4, 1 ', 6' -trideoxygalactosucrosose).

In one aspect of the present invention, a Vilsmeier reagent is prepared by adding a chlorinating agent to a solvent comprising DMF or a mixture of DMF and one or more other organic solvents such as toluene, cyclohexane, dichloroethane (dichloroethane), chloroform and carbon tetrachloride. Sucrose-6-ester is dissolved in a solvent. Before mixing, the Vilsmeier reagent and the DMF solution of sucrose-6-ester are frozen to below 0 ℃. The Vilsmeier reagent was then added dropwise to the DMF solution of sucrose-6-ester to keep the reaction temperature below 5 ℃. After the addition of the vilsmeier reagent was complete, the reaction mixture was stirred for 2 hours at a temperature below 5 ℃. The reaction mixture was warmed to room temperature and kept at room temperature for 2 hours. The reaction mixture was then heated to 110 ℃ for 2-3 hours and refluxed at 110 ℃ for 3 hours. The reaction mixture was then allowed to cool to room temperature. The pH of the reaction mixture was adjusted to 8-9 with aqueous ammonia/methanol solution (1: 1) and then to 6-7 with glacial acetic acid (glaciatic acid). After most of the solvent was removed by distillation under reduced pressure, the sucrose-6-ester was extracted with ethyl acetate and water. The combined organic phases were distilled under reduced pressure to obtain sucralose-6-ester syrup. The sucralose-6-ester is then converted to sucralose by a de-esterification reaction with sodium methoxide/methanol or sodium ethoxide/ethanol.

In another aspect of the invention, the chlorinating agent may also be dissolved in one or more organic solvents such as toluene, cyclohexane, dichloroethane, chloroform and carbon tetrachloride, before being added to the DMF solution of sucrose-6-acetate, while the other steps are kept unchanged.

The chlorinating agent may be selected from triphenylhydrazine (triphenylhydrazine), phosphorus pentachloride (phosphorus chloride), thionyl chloride, phosgene and oxalyl chloride (oxalyl chloride). Triphosgene (bis (trichloromethyl) carbonate, BTC) is preferably used. BTC is safe and convenient to use, and it does not cause problems such as pollution and corrosion.

Preferably, the concentration of sucrose-6-ester is 0.1 to 0.11 mol/L.

The molar equivalent ratio (ME) of chlorinating agent to sucrose-6-ester is 2.8-3.5.

The reaction may be carried out in a vacuum environment to avoid oxidation of the reaction mixture by oxygen in air. Alternatively, a low boiling organic solvent such as cyclohexane, dichloroethane, ethyl acetate, chloroform and carbon tetrachloride may be refluxed with the reaction mixture to avoid oxidation.

[ examples ] A method for producing a compound

The first embodiment is as follows: chlorination of sucrose-6-ester with triphosgene in DMF

Sucrose-6-acetate (30g, 0.08mol) was dissolved in DMF (300mL) and the solution temperature was kept below 0 ℃. BTC (80g, 0.27mol) was slowly added to DMF (500ml) at below 0 ℃ to prepare Vilsmeier reagent. The Vilsmeier reagent was then slowly added to the DMF solution of sucrose-6-ethyl ester and the reaction temperature was kept below 5 ℃. The reaction was stirred at a temperature below 5 ℃ for 2 hours, followed by stirring at ambient temperature for 2 hours. The reaction mixture was slowly heated to 110 ℃ and refluxed at 110 ℃ for 3 hours. After the reaction was completed, the reaction mixture was naturally cooled to normal temperature. The reaction mixture was neutralized with aqueous ammonia/methanol solution (1: 1, 400mL) to pH 8-9, stirred at ambient temperature for 5 minutes, and then adjusted to pH 6-7 with glacial acetic acid. Most of the solvent was distilled off under reduced pressure. To the remaining solution were then added distilled water (100mL) and ethyl acetate (500 mL). The mixture was stirred at room temperature for 1 hour and filtered. The filter cake was washed with ethyl acetate (150 mL). The aqueous phase of the filtrate was extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with saturated brine (2X 100mL) and then concentrated to about 400mL by distillation at a temperature below 60 ℃ under reduced pressure. The remaining solution was decolorized with activated charcoal (10g), and the solution was filtered and concentrated to give a syrup (40g, containing 20g (0.045mol) of sucralose-6-acetate, yield 56%).

Example two: chlorination of sucrose-6-ester with BTC dissolved in toluene

The procedure was as in example one, except that a toluene solution of BTC was directly added to a DMF solution of sucrose-6-acetate (30g, 0.08mol) to start the chlorination reaction. A toluene solution of BTC was prepared by dissolving BTC (80g, 0.27mol) in toluene (400mL) cooled to below 0 ℃. The reaction product was a syrup (0.05mol) containing 22g of sucralose-6-acetate, with a yield of 62.5%.

Example three: preparation of sucralose from sucralose-6-acetate

Sodium methoxide/methanol solution (containing 4g, 0.015mol of sodium methoxide) at 20% concentration was added to a 15 ℃ solution of sucralose-6-acetate (10g, 0.023mol) in methanol (100 mL). The mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with a hydrogen strong acid ion exchange resin (hydrogen strong acid ion exchange resin) which was washed with methanol and filtered. The filtrate was concentrated under reduced pressure to a soft foam at a temperature below 30 ℃. The foam was dissolved in distilled water (100mL), and the solution was extracted with ethyl acetate (50 mL). The aqueous phase was then decolorized with activated charcoal (0.5g), then filtered to remove the activated charcoal and washed with distilled water (2X 300 mL). The filtrate was concentrated to a syrup by distillation under reduced pressure at room temperature. Distilled water (8mL) was added to the slurry at 80 ℃ to dissolve the syrup. After the solution was cooled to below 20 ℃, seed crystals were added thereto. The crystals formed were obtained by filtration, washed with a small amount of ice water, then dried, and finally dried in a crystallizing dish at 45-50 ℃ under reduced pressure to obtain sucralose (5g, 0.013mol, yield 86%).

As mentioned above, the above description is intended only to illustrate various embodiments of the present invention. The specific variations discussed above are not to be construed as limitations on the scope of the invention. Various equivalents, changes, and modifications which do not depart from the scope of the invention will become apparent to those skilled in the art, and it is understood that such equivalent embodiments are to be included within the scope of the invention. All references cited herein are fully incorporated by reference in their entirety.

The claims (modification according to treaty clause 19)

1. A method of making sucralose comprising the step of chlorinating a sucrose-6-ester with a chlorinated component comprising BTC.

2. The method of claim 1, wherein the chlorinated component comprises at least one organic solvent.

3. The method of claim 1, wherein the chlorinated component comprises at least one of DMF, cyclohexane, toluene, dichloroethane, chloroform, carbon tetrachloride, and ethyl acetate, or any combination thereof.

4. The method of claim 1, wherein the chlorinated component comprises a unidimensional hermimel reagent.

5. The method of claim 4, wherein the Vilsmeier reagent is prepared by dissolving BTC in a DMF component, wherein the DMF component comprises DMF and optionally but not necessarily the DMF component further comprises one or more organic solvents.

6. The method of claim 1, wherein the step of chlorinating the sucrose-6-ester with the chlorinated component comprises: dissolving BTC in one or more organic solvents; and adding the BTC solution to a DMF solution of sucrose-6-ester.

7. The method of claim 6, wherein the organic solvent is selected from the group consisting of DMF, cyclohexane, toluene, dichloroethane, chloroform, carbon tetrachloride and ethyl acetate.

8. The method of claim 1, wherein the molar equivalent ratio of BTC to sucrose-6-ester is from about 2.8: 1 to about 3.5: 1.

9. The process of claim 1, wherein the chlorination reaction is carried out at atmospheric or reduced pressure.

10. The method of claim 1, further comprising:

cooling the chlorinated component to below about 0 ℃ prior to contacting the chlorinated component with the sucrose-6-ester;

maintaining a temperature below about 5 ℃ when the chlorinated component is contacted with the sucrose-6-ester to form a first mixture; and

the first mixture was warmed to room temperature.

11. The method of claim 10, further comprising:

maintaining the first mixture at room temperature for about 3 hours to form a second mixture;

heating the second mixture to about 110 ℃; and

the second mixture was held at about 110 ℃ for about 3 hours.

12. A process for the preparation of sucralose comprising the step of chlorinating sucrose-6-ester with Vilsmeier reagent prepared by dissolving BTC in DMF, wherein the molar equivalent ratio of BTC to sucrose-6-ester is from about 2.8: 1 to about 3.5: 1.

Claims (10)

1. A method for preparing sucralose from sucrose-6-ester comprising preparing vilsmeier reagent as a chlorinating agent with BTC.

2. The method of claim 1, further comprising dissolving BTC in DMF to prepare the vilsmeier reagent.

3. The method of claim 1, wherein the Vilsmeier reagent is prepared by dissolving BTC in DMF and one or more organic solvents.

4. The method of claim 1, comprising dissolving BTC in one or more organic solvents and adding the BTC solution obtained to a DMF solution of sucrose-6-ester.

5. The method of claim 4, wherein the organic solvent is selected from the group consisting of DMF, cyclohexane, toluene, dichloroethane, chloroform, carbon tetrachloride, and ethyl acetate.

6. The method of claim 1, wherein the molar equivalent ratio of BTC to sucrose-6-ester is from 2.8: 1 to 3.5: 1.

7. The process of claim 1, wherein the chlorination reaction is carried out at atmospheric pressure or reduced pressure.

8. The method of claim 1, further comprising cooling the reagent to less than 0 ℃ prior to contacting the reagent with the sucrose-6-ester, controlling the temperature of the reagent while contacting the reagent with the sucrose-6-ester to form a first mixture to less than 5 ℃, and returning the first mixture to room temperature.

9. The method of claim 8, further comprising maintaining the temperature of the first mixture at room temperature for 3 hours to form a second mixture, heating the second mixture to 110 ℃ and maintaining it at 110 ℃ for three hours.

10. A method of making sucralose from a sucrose-6-ester comprising:

vilsmeier reagent for chlorination is prepared with BTC, wherein the Vilsmeier reagent is prepared by dissolving BTC in DMF, wherein the molar equivalent ratio of BTC to sucrose-6-ester is about 2.8: 1 to 3.5: 1.