Chlorination of carbohydrates and carbohydrate derivatives

Abstract

Disclosed is a method for chlorinating a carbohydrate or a derivative thereof to produce a polychlorinated carbohydrate or a derivative thereof, such as sucralose, the method involves (i) reacting the carbohydrate or derivative thereof with a chlorinating agent to obtain a reaction mixture comprising said polychlorinated carbohydrate or derivative thereof and at least one under-chlorinated carbohydrate or derivative thereof, (ii) returning the at least one under-chlorinated carbohydrate or derivative thereof to a chlorinating step and further chlorinating the at least one under-chlorinated carbohydrate or derivative thereof to obtain the desired polychlorinated carbohydrate or derivative thereof; and (iii) optionally repeating steps (i) and (ii) “n” times where n≧1. The polychlorinated carbohydrate or a derivative thereof is obtained in high yields.

1 . A method for chlorinating a carbohydrate or a derivative thereof, wherein said carbohydrate or derivative thereof has two or more hydroxyl groups, to produce a polychlorinated carbohydrate or a derivative thereof, said polychlorinated carbohydrate or a derivative thereof having a desired number of chlorine atoms replacing two or more of the hydroxyl groups at desired locations in its molecular structure, the method comprising:
 (i) reacting the carbohydrate or derivative thereof with a chlorinating agent to obtain a reaction mixture comprising said polychlorinated carbohydrate or derivative thereof and at least one under-chlorinated carbohydrate or derivative thereof;   (ii) returning the at least one under-chlorinated carbohydrate or derivative thereof to a chlorinating step and further chlorinating the at least one under-chlorinated carbohydrate or derivative thereof to obtain the desired polychlorinated carbohydrate or derivative thereof; and   (iii) optionally repeating steps (i) and (ii) “n” times where n≧1.   
     
     
         2 . The method of  claim 1 , further comprising:
 (iv) quenching at least a portion of the reaction mixture from step (i) to obtain a quenched reaction mixture and   (v) isolating a product mixture comprising polychlorinated carbohydrate or derivative thereof and at least one under-chlorinated carbohydrate or derivative thereof from the quenched reaction mixture.   
     
     
         3 . The method of  claim 1 , wherein the at least one under-chlorinated carbohydrate or derivative thereof is returned to step (i) for further chlorination. 
     
     
         4 . The method of  claim 1 , wherein the further chlorination of the at least one under-chlorinated carbohydrate or derivative thereof takes place in a vessel separate from the vessel where step (i) takes place. 
     
     
         5 . The method of  claim 1 , wherein the further chlorination of the at least one under-chlorinated carbohydrate or derivative thereof takes place in the same vessel where step (i) takes place. 
     
     
         6 . The method of  claim 2 , wherein in step (v), the product mixture is isolated from the quenched reaction mixture by solvent extraction. 
     
     
         7 . The method of  claim 2 , further comprising: (vi) separating the product mixture isolated in step (v) into (a) a first fraction comprising the polychlorinated carbohydrate or derivative thereof and (b) a second fraction comprising at least one under-chlorinated carbohydrate or derivative thereof. 
     
     
         8 . The method of  claim 1 , wherein the polychlorinated carbohydrate or derivative thereof, under-chlorinated carbohydrate or derivative thereof, or a mixture thereof, is optionally combined with additional carbohydrate or derivative thereof and returned to a chlorinating step or to step (i). 
     
     
         9 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the polychlorinated carbohydrate derivative is 4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester of galactosucrose (TGS-6E). 
     
     
         13 . The method of  claim 1 , wherein the polychlorinated carbohydrate ester or the under-chlorinated ester is of the formula:
   M—OC(═O)R′,
   wherein R′ comprises a hydrophobic group or a hydrophobic polymer and M is the moiety completing the rest of the polychlorinated carbohydrate ester or the under-chlorinated ester.   
     
     
         14 . The method of  claim 13 , wherein R′ comprises a hydrophobic group or a hydrophobic polymer such that the polychlorinated carbohydrate ester or the under-chlorinated ester has an octanol-water partition coefficient cLogP of −0.5 or greater. 
     
     
         15 . The method of  claim 14 , wherein the polychlorinated carbohydrate ester or the under-chlorinated carbohydrate ester has an octanol-water partition coefficient cLogP of 0 or greater than 0. 
     
     
         16 . The method of  claim 15 , wherein R′ is phenyl. 
     
     
         17 . The method of  claim 1 , wherein the chlorinating agent is an acid chloride or an activated acid chloride. 
     
     
         18 . The method of  claim 17 , wherein the acid chloride is selected from the group consisting of thionyl chloride, sulfuryl chloride, phosgene, phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride, and bis(trichloromethyl)carbonate. 
     
     
         19 . The method of  claim 17 , wherein the activated acid chloride is a Vilsmeier Reagent [or Arnold's reagent] having the formula: [XYC═N + R 2 ]Cl − , wherein X is hydrogen, aryl, or alkyl, wherein the aryl or alkyl is optionally substituted with a halogen, alkoxy, thioalkoxy, amido, or cyano; Y is a leaving group; and R is hydrogen or alkyl which is optionally substituted with halogen, alkoxy, thioalkoxy, amido, or cyano. 
     
     
         20 - 24 . (canceled) 
     
     
         25 . A method for chlorinating a carbohydrate or a derivative thereof, wherein said carbohydrate or derivative thereof has two or more hydroxyl groups, to obtain a polychlorinated carbohydrate or derivative thereof, said polychlorinated carbohydrate or derivative thereof having a desired number of chlorine atoms replacing two or more of the hydroxyl groups at desired locations in its molecular structure, the method comprising:
 (a) dissolving the carbohydrate or derivative thereof in an aprotic solvent system to obtain a solution comprising the carbohydrate or derivative thereof;   (b) combining the solution comprising the carbohydrate or derivative thereof from step (i) with a chlorinating agent to obtain a chlorination mixture;   (c) heating the chlorination mixture to obtain a mixture of chlorinated carbohydrates or derivatives thereof comprising the desired polychlorinated carbohydrate or derivative thereof and at least one under-chlorinated carbohydrate or derivative thereof having less than the desired number of chlorine atoms;   (d) returning at least one under-chlorinated carbohydrate or derivative thereof to a chlorinating step so as to further chlorinate the at least one under-chlorinated carbohydrate or derivative thereof; and optionally   (e) repeating steps (b)-(d) “n” times where n≧1.   
     
     
         26 . The method of  claim 25 , further comprising (f) separating the polychlorinated carbohydrate or derivative thereof from the at least one under-chlorinated carbohydrates or derivatives thereof. 
     
     
         27 . The method of  claim 25 , wherein the at least one under-chlorinated carbohydrate or derivative thereof is returned to step (a) for further chlorination. 
     
     
         28 . (canceled) 
     
     
         29 . A method of preparing sucralose comprising de-esterifying the polychlorinated sucrose 6-ester obtained according to  claim 1  to obtain sucralose. 
     
     
         30 . (canceled)