KR850000078B1 - Process for the preparation of 4,1',6',trichloro-4,1',6'-trideoxy-galactosucrose - Google Patents

Abstract

The title compd., useful as a powerful sweetening material, was prepd. by the reaction of 2,3,4,3',4'-penta-o-acetylsucrose solution with weak acid, which was isomerized. Then, the mixture was chlorinated and deacetylated at the 4,1' and 6'-position. Thus, 2g 2,3,4,3',4'-penta-o-acetymsucrose was dissolved with isobutylketone and added to 1ml acetic acid, which was heated at 126≰ for 3hrs. to give 1.5g 2,3,6,3',4'-penta-o-acetyl sucrose.

Description

Preparation of 4,1 ', 6'-trichloro-4,1'6'-trideoxy-galactose sucrose

The present invention relates to the preparation of 2,3,6,3 ', 4'-penta-0-acetyl sucrose, which is a powerful sweetener 4,1', 6'-trichloro-4,1 ', 6' Trideoxy galactosucrose, in particular 1,6-dichloro-1,6-dideoxy-β-D-furactofuranosyl 4-chloro-4-deoxy-α-D-galactopyranoside It is about the manufacturing method of. Trichloro galacto sucrose, hereinafter referred to as TGS, is a powerful sweetener that provides several hundred times the sweetness of sucrose. Sweet compositions containing them and their use as sweeteners are described in British Patent No. 1,543,167.

The biggest problem with TGS synthesis relates to the chlorination of the 4,1 'and 6' positions of the sucrose molecule at other positions without chlorination. One way to achieve this is to conveniently chlorinate sucrose derivatives having 2,3,6,3 'and 4' positions that are blocked by esterification, so that only the 4,1 'and 6' positions are useful for chlorination. . The chlorination of this intermediate is three hydroxy groups, one of which is a reactive primary hydroxyl group (6'-group), one of which is a significantly less reactive primary group (1'-group) and the other of which is 2 This is complicated by the fact that the class hydroxy group is substituted with a chlorine atom.

The method described by Fairc lough et al., Carbohydrate Research, 40 (1975) 285-298 is known to form 6,1'-6'-tritrityl derivatives of sucrose and to hyperacetylate molecules. It is composed. The tritrityl penta-acetate obtained is detritritylated under conditions such that the acetyl group in the 4-position is moved to the 6-position which is empty by removing the trityl group in the first step. The detritylation reaction was first reported by Mckeown and his colleagues (Canadian Journal of chemistry 35 (1957) 28-36), in which tritrityl penta-acetate was dissolved in glacial acetic acid and heated for a period of time. It is composed. Under these conditions, the yield of detritylated pentaacetate is generally about 55% or less of theory, and low yields are clearly caused by the formation of various corresponding byproducts. Meekwang and his colleagues reported that optimal yields could be achieved by refluxing for about 30 minutes. At 120 minutes reflux time less than 30 minutes or longer reduces the yield until practically no desired product is obtained.

Another process for moving 4-acetyl groups to the 6-position has been described by Bredereck and his colleagues (Chem. Ber., 91 (1958) 2824). In a second step process, triisyl penta-acetate is reacted with hydrogen bromide in acetic acid to selectively detritylate upon cooling to provide a non-isomerized penta acetate. Treatment with glacial acetic acid at an elevated temperature in turn yielded isomerized penta-acetate in a relatively low yield (24%). The overall yield when tritrityl penta acetate was reacted with isomerized penta-acetate was about 19%.

Detritalization and acetyl transfer bound from these publications yield higher yields of isomerized penta-acetate than separate detritylation and subsequent isomerization.

Isomerization step (1) is carried out by treating a 2,3,4,3 ', 4'-penta-0-acetyl sucrose solution with a weak acid in an inert solvent at an elevated temperature according to the present invention. 1) isomerized 2,3,4,3'4'-penta-acetyl sucrose to 2,3,6,3 ', 4'-penta-0-acetyl sucrose and 2) 4,1' and 4,1 ', 6'-trichloro-4,1', 6'-trideoxy galact-suc, consisting of chlorinating the isomerized acetate at the 6'-position and 3) deacetylating the chlorinated product. Provided is a method for preparing a loose.

The weak acid is preferably a carboxylic acid, especially an aliphatic carboxylic acid such as acetic acid. Acids having acid strengths in the same state as acetic acid are generally preferred under the conditions used.

The reaction temperature should be raised above room temperature to provide an acceptable reaction temperature. Generally about 80 ° -150 ° C. is suitable and temperatures of 100 ° -130 ° C. are preferred.

Inert solvents are some of the solvents for penta-0-acetyl sucrose that remain liquid at selected elevated temperatures, such as in the range of 100-140 ° C. Preference is given to ketone solvents, in particular methylisobutyl ketone which is refluxed at about 126 ° C. High boiling ester solvents such as n-butyl acetate are also useful. Of particular interest are aromatic hydrocarbons such as toluene or xylene.

Dilute solutions of acids in solvents, such as 2-10% by weight, in particular 5% by weight, are suitable. The degree of dilution is suitable for reaction with molten sucrose penta-acetate at concentrations up to 30% by weight, such as about 20%.

The reaction time, of course, depends on the temperature selected, but at a temperature of about 110-130 ° C., the reaction time of 2-4 hours was found to be satisfactory.

In the reaction according to the invention, a yield of at least 75% of theory can be achieved in step (1). Total yield of about 70% from tritrityl penta-acetate because detritylation of 6,1 ', 6'-tritrityl sucrose penta-acetate can be achieved with a yield of 95% or higher This is provided. De-tritylation of 6,1 ', 6'-tritrityl sucrose penta acetate can be carried out simply by treatment with acid in an inert solvent at low temperatures, such as about 0 ° C. Thus, upon mixing with glacial acetic acid, ketone solvents such as methyl isobutyl ketone are acidified again with inorganic acids such as hydrochloric acid to provide a convenient acid medium for detritylation.

As mentioned above, other important process steps in the synthesis of TGS include chlorination of the 4,1 'and 6'-positions of sucrose penta acetate. It is necessary to use chlorinating agents capable of chlorination at all three positions. Insufficient chlorination results in a product consisting of a mixture of chlorinated derivatives that are difficult to separate as well as low yield.

Many known chlorinating agents used in the carbohydrate field are insufficient to provide trichloro derivatives in high yields and sulfuryl chloride is used in conventional methods. This chlorinating agent is used as a combination of an organic amine base such as pyridine and a chlorinated hydrocarbon such as chloroform.

The reaction is treated by the formation of chlorosulfate esters and then degraded to form chloro derivatives. The method used by Fair clough and his colleagues (op.cit) employs a slight excess of sulfuryl chloride to insure chlorination and in some cases raises the low temperature, eg, -75 ° C to room temperature. Is described. The inventors have found that excess suryl chloride (e.g., 2.5 ml per gram of sucrose penta acetate as opposed to about 1 ml per 1 ml of pentaacetate) and higher reaction temperatures (e.g., 20-about 55 ° C or more) have improved yields, typically It is found that about 75% will be provided.

According to another feature of the invention, as described above, the chlorination step (2) is carried out using 2-5 ml of sulfuryl chloride per gram of sucrose penta acetate at a reaction temperature of 20-80 ° C. The same method for producing TGS is provided.

However, one disadvantage of this process is the fact that organic amines, in particular pyridine, lead to the formation of unwanted by-products which are difficult to separate in the direction of chlorination by sulfuryl chloride. The inventors have found that some other chlorinating agent, which was not expected to provide the desired product, could actually be used to provide high yields in a simple reaction process.

Chlorinating agents derived from triarylphosphines and carbon tetrachloride are known in the art for chlorinated carbohydrates. Usually, reagents are used under relatively mild conditions to obtain selective chlorination of only the more reactive primary hydroxy groups. Thus, when 1 molar equivalent of a hydroxy compound is reacted with 1.5 molar equivalents of carbon tetrachloride and 3 molar equivalents of triphenylphosphine in phytidine at 0 ° C., the sucrose is 6,6'-dichloro-6,6'- While uridine, methyl-α-D-glucopyranoside, inosine and other similar carbohydrates are obtained with dideoxy sucrose, the primary hydroxy is optionally substituted by an atom (Kashem et al., Carbohydrate Research 61 1978). 511-518) chlorinated derivatives are provided. This type of reaction process is the usual method in which reagents are used and reagents are generally employed as selective chlorinating agents for the more reactive first position. Under more effective conditions, ie, further chlorinating agent and high temperature, sucrose appears to decompose without chlorination together in the 1'- and 4-positions.

Changes in reagents were reported by Regen & Lee (J. Org. Chem. 40 1669-1670, 1975). In this case, one aryl substituent on the phosphine molecule is replaced by a styrene group of crosslinked polystyrene. The reagent is thus a resin bound triarylphosphine which actually functions in the same way as the original triarylphosphine. The great advantage of immobilized reagents is that they can be easily removed from the reactants and regenerate by-products (in the form of unreacted or triarylphosphine oxide by-products).

The inventors have found that the primary chlorinating agent in the form of triarylphosphine / carbon tetrachloride is 2,3,6,3 ', 4' in a process for producing TGS under conditions such that only the first reactive hydroxyl group can be chlorinated. Can be used to chlorinate penta-0-acetyl sucrose. Surprisingly, unlike the 1'-first hydroxyl group being substituted with a chlorine atom, the 1'-hydroxy group in sucrose does not react with this reagent and the second 4-hydroxy group is chlorine like 6'-hydroxy. It is also substituted by an atom.

According to another feature of the invention, the molar equivalents of sucrose pentaacetate in an organic amine base at room temperature up to the reflux temperature of the system, preferably at a molar equivalent of about 2 molar equivalents of phosphine relative to 1 molar equivalent of carbon tetrachloride Provided is a method for preparing TGS described above, wherein the penta acetate of step (2) is combined with carbon tetrachloride and then reacted with a phosphine derivative of formula (1) using at least 6 molar equivalents of a phosphine derivative. .

Phosphine derivatives can be separated into the following two forms: 1) phosphine derivatives of formula (1) wherein R ¹ , R ² and R ³ are all aryl groups such as phenyl or alkylphenyl groups 2) R ¹ and R ² Is a phenyl group bonded to a polymer hydrocarbon, ie, an aryl group bonded to a resin such as a phenyl group of a polystyrene resin, while R ³ is as described in the above 1) form.

(2) Reagents in the form of Regen and Lee op. cit, ie polystyryldiphenyl phosphine. This reagent may be regarded as a triphenyl phosphine bound by one phenyl group to the resin or as a polystyrene resin in which part of the phenyl group is substituted with a diphenylphosphino group, and the triphenyl phosphine itself may be selected as a reagent. Can be.

The organoamine base is a tertiary amine, in particular a heterocycle tertiary amine such as pyridine. Generally, the conditions when using a 2 molar ratio of phosphine derivatives per mole of carbon tetrachloride in a base such as pyridine are known conditions for selective chlorination in the first center. Indeed, only the 6- and 6'-positions are chlorinated when these conditions are used for sucrose itself. Surprisingly, the inventors have found that chlorination at three useful centers of sucrose penta esters involves that the reagents have less effect on the 1-position and the second 4-position at temperatures from room temperature to the reflux temperature of the system. It can be found. The product is obtained in high yield and indeed other chlorinated derivatives are liberated.

The reaction mixture is conveniently prepared by adding a lower alkanol such as methanol to the reaction mixture and the reaction mixture is evaporated to dryness. The residue is recrystallized from a suitable solvent and washed with acid to remove basic material. Phosphine derivatives are resin-bound unreacted starting materials and phosphine oxide by-products can be removed simply by filtration of the reaction mixture.

Another kind of chlorinating agent that can be used in step (2) of the process of the present invention is N, N-dialkyl (chloromethaneimium) chloride of the following general formula (2).

This type of reagent is prepared by reacting an inorganic acid chloride with N, N-dialkylformamide or N, N-dialkylacetamide. The inorganic acid chloride may typically be phosphorus penta chloride, phosgene, or thionyl chloride.

This type of reagent is particularly safe in the 4,1'- and 6'-positions of sucrose molecules, such as acidic reagents, which are known for their specificity, such as chlorine agents of the more active first hydroxy compounds in general. It is surprising that it can be chlorinated. Thus, for example, when N, N-dimethyl (chloromethaneimium) chloride is reacted with uridine, 5-chloro-uridine, no apparent chlorination occurs at two possible second positions (Dods & Roth, Tetrahedron Letters 165). -168, 1969). Moreover, the reaction of the saccharides in three of the first hydroxyl group and the useful second hydroxy net was protected by acetal formation to leave the one obtained with the second hydroxy removed, thus indeed a chlorinated product with the first hydroxy. Replaced with chlorine and had protective acetal moved to the second position. In particular, 1,2: 5,6-di-0-isopropylidene-α-D-glucofuranos is 6-chloro-6-deoxy-1,2: 3,5-di- in a yield of at least 70%. 0-isopropylidene-α-D-glucofuranose is provided. (Hanessian and Plessas, J. Org. Chem. 34, 2163-2170, 1969).

We have found that the reagent in question is reacted with 2,3,6,3 ', 4'-penta-0-acetylsucrose to provide the corresponding trichloro derivative (i.e., TGS pentaacetate) in a yield of at least 80%. I learned.

According to another feature of the invention, the process according to the invention for the preparation of TGS as described above is carried out in step (2) with pentaacetate and an inorganic acid chloride of the formula R ₂ NCOX, wherein X and R are as described above. It is formed by reacting with N, N-dialkylami and then reacting with the reagent of formula (2).

The reaction is preferably carried out with a slight excess of chlorinating agent (such as about 4 moles of reagent per mole of sucrose penta-ester) in an inert solvent. The inert solvent may be, for example, a chlorinated hydrocarbon such as 1,2,2-trichloroethane or an aromatic hydrocarbon solvent such as toluene. The reaction is conveniently carried out under reflux, preferably under nitrogen atmosphere to maintain anhydrous reaction conditions. The reaction mixture can be carried out very simply by evaporation to dryness and recrystallization from a solvent such as ethanol, preferably via a pigment removal step which is filtered through charcoal.

The reagent of formula (2) is conveniently formed in situ in the reaction vessel by directly contacting the inorganic acid chloride with the amine. Alternatively, the reagent may be preformed and added to the reaction vessel. Reagent formation can be accomplished by reacting acid chlorides such as phosphorus pentachloride or thionyl chloride in stoichiometric amounts or with excess amide as solvent. In contrast, since the amide is regenerated during the chlorination reaction, a small amount of acid chloride and a catalytic amount of amide can be used, so that the chlorinating agent is always reformed during the reaction.

Therefore, this chlorination method is a simple, quick and easy reaction that provides a high yield of the desired chlorinated sucrose ester.

Another kind of chlorinating agent used in step (2) of the process of the present invention consists of tri-substituted dichlorophosphorane which can sometimes provide a high yield of product at the original room temperature in a selective and rapid manner.

According to another feature of the invention, the process according to the invention for the production of TGS by the above-mentioned method is characterized in that the penta acetate is reacted with a dichlorophosphoran derivative of the following general formula (3).

Food,

Reagent of the general formula (3) wherein Y is an aryloxy group can be prepared by reacting triaryl phosphite of general formula Y ₃ P (wherein Y is an aryloxy group) with gaseous chlorine. This reaction can be carried out simply by blowing chlorine gas into the liquid triaryl phosphite. Alternatively, the gas can be bubbled into a triaryl phosphite solution in an inert solvent. Reagent of general formula (3), wherein Y is an aryl group, can be similarly prepared by reacting triaryl phosphine of general formula Y ₃ P (wherein Y is an aryl group) with chlorine gas. In this case, however, the solvent for the triarylphosphine is preferably chlorinated hydrocarbons such as carbon tetrachloride, which can be subsequently added before using the reagents.

Triaryloxy dichlorophosphorane is a known class of compounds. Thus, for example, triphenoxy dichlorophosphorane is known by Chemical Abstracts as CAC Registration No. 14593-07-9 and is a good chlorinating agent for alcohols, according to Coe et al. (J. Chem. Soc. 1954 P 2281). However, this compound has been reported for preparing polymers when condensed with dihydroxy compounds. (Osake Kogyo Gijutsu Shikensho Kiho, 1967, 18, 117-122). It is therefore surprising that this kind of reagent can safely chlorine the three hydroxyl groups of the sucrose penta acetate described above.

Triaryldichlorophosphorane is also a known kind of compound. Triphenyldichlorophosphorane is Chemical Abstracts CAS Registration No. 2526 64-9 and is described, for example, as Wiley et al., J. Am. Chem. Soc 86, 964, (1964). It is also used for the separation of ethers and the chlorination of aldehydes and ketones, and is therefore expected to be unstable for the chlorination of sucrose derivatives.

The reagent of formula (3) is preferably formed immediately before use of chlorinated triarylphosphite or triarylphosphine as described above. Chlorination of the sugar esters is conveniently carried out in a basic solvent such as a tertiary amine such as pyridine. The reaction with triaryloxydichlorophosphorane is conveniently carried out at room temperature or higher, such as 15-60 ° C. The reaction is mild exothermic and can be cooled if necessary, but with triaryl dichlorophosphoran Silver requires a high temperature of, for example, 50-95 ° C.

The reaction mixture can be conveniently carried out by pouring it into water and extracting with an organic solvent such as dichloromethane. The extract is washed with acid and base, dried and evaporated to give a product which can be purified again, for example by chromatography on silica gel, to give a yield of nearly 80% of trichlorester.

Hereinafter, the present invention will be described in detail with reference to Examples. All temperatures are ℃ and Amberlite and Amberlyst are registered trademarks.

Example 1

Preparation of 2,3,6,3 ', 4'-penta-0-acetyl sucrose (starting material)

(a) Use of methyl isobutyl ketone

2,3,4,3 ', 4'-penta-0-acetim Sucrose (2 g) was dissolved in isobutyl ketone (20 ml) and acetic acid (1 ml) was added. The mixture was heated at reflux (about 126 °) for 3 hours. 1.5 g (75%) of 2,3,6,3 ', 4'-penta-0-acetyl sucrose was obtained upon cooling the determined product.

(b) using toluene

2,3,4,3 ', 4'-penta-0-acetyl sucrose (2 g; purity 83.63%) and glacial acetic acid (0.2 L) were added to toluene (10.0 L) and the mixture was heated to reflux for 6 hours. Or kept under reflux until acetyl transfer was complete. The solution was cooled to room temperature, the precipitate was filtered off, washed with fresh toluene and dried in a vacuum oven at 40 ° C., yielding 2,3,6,3 ', 4'-penta-0-acetyl sucrose (15.90) with a yield of 83.3% or more. g; purity 87.65%) was obtained.

Example 2

Preparation of 4,1 ', 6'-trichloro-4,1', 6'-trideoxo galactose sucrose

One Step Tritylation and Acetylation

Sucrose (100 g) and trityl chloride (270 g) were added to anhydrous pyridine (600 ml) and stirred with heating at 65 ° C. for 18 hours. After pyridine was removed in vacuo, the syrup product was acetylated by addition of acetic anhydride (600 ml) with stirring for 12 hours at room temperature. The reaction mixture was poured into ice water with stirring and the precipitated product was filtered off and dried to constant weight. A solution of this precipitate in dichloromethane (1 L) was dried over sodium sulfate and concentrated in syrup, repeatedly dissolved in methanol, diluted with toluene and concentrated to remove traces of pyridine. The product was determined from acetone-methanol (1: 9, 500 ml) at 0 ° C. to give 6,1 ′, 6′-tri-0-trityl sucrose penta-acetate (260 g, 70%).

Step 2a Detritylation

6,1 ', 6'-tri-0-trityl sucrose penta-acetate (50 g) was dissolved in dichloromethane (500 ml) and acetic acid (500 ml) and the solution was cooled to 0 ° C and concentrated hydrochloric acid (10 ml) was added. ) Was added. The reaction mixture was stirred at 0 ° C. for 2 hours and then neutralized by addition of Amerlite IR 45 (OM) resin. The reaction mixture was stirred for 1 h and concentrated in syrup to add methanol (200 ml). After 3 hours at 0 ° C., precipitated triphenylmethanol (27.6 g) was filtered off and the solution was concentrated to syrup. Acetone (400 ml) was added and the solution was decolorized with charcoal and concentrated with dilute syrup. Ether (300 ml) was added and 2,3,4,3 ', 4'-penta-0-acetyl sucrose was determined at room temperature (yield 20.5 g, 95%).

Stage 2b Acetyl Transfer

2,3,4,3 ', 4'-penta-0-acetyl sucrose (20 g) was dissolved in methyl isobutyl ketone (200 ml) and acetic acid (10 ml) was added. The reaction mixture was heated at reflux for 2.75 h under reflux. The reaction mixture was cooled to 60 ° C. and colored oil ether (60-80 °) (20 ml) was added. 2,3,6,3 ', 4'-penta-0-acetyl sucrose was again determined upon cooling. The crystalline product was filtered off for 16 hours at 0 ° and washed with diethyl ether to dryness. Yield 15.2 g (75%)

Chlorination of 3-Step Sulfuryl Chloride

A solution of sulfuryl chloride (15 ml) in 1,2-dichloroethane (15 ml) was added to 2,3,6,3 ', 4'-penta-0-acetyl sucrose (5 g) in pyridine (15 ml) without external cooling. ) And 1,2-dichloroethane (15 ml). The exothermic reaction raised the temperature to 45-55 °. The reaction mixture was heated at reflux for 4 hours, cooled and dichloroethane (50 ml) was added. The resulting solution was washed successively with 10% hydrochloric acid (100 ml), water and 10% sodium hydrocarbon solution until neutral. The organic phase was dried and concentrated in syrup to crystallize from toluene (25 ml) to afford 4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose penta-acetate.

Yield: 4.1 g (75%)

Four steps of deacetylation

4,1 ', 6'-trichloro-4,1'6'-trideoxygalactose sucrose pentaacetate (20 g) was dissolved in methanol (200 ml) and sodium methoxide in 1.0 N methanol in methanol. Was added until pH 9. The reaction mixture was stirred at rt for 4 h, neutralized with Amberlyst ± 15 (H ⁺ ) ion exchange resin, filtered and concentrated to dryness. The solid organisms were dissolved in distilled water (60 ml) and the given cloudy solution was filtered to give a clear colorless solution. An aqueous solution of TGS was concentrated to dryness. Yield = 12.6 g (96%) total yield from sucrose was 36%.

Example 3

Chlorination using polymer bound triphenylphosphine

Carbon tetrachloride (2 g, 3 mol) in polymer bound triphenylphosphine (Regen & Lee J. Org. Chem. 40 (1975) 1669) (8 g, 6 molar equivalents, substituted almost 80%) at 0 ° C. Equivalents) was added followed by 2,3,6,3 ', 4'-penta-0-acetylsucrose (2,3 g, 1 molar equivalent).

The mixture was filtered by heating to 80 ° C. for 4 h, cooling. Polymer beads were washed with dichloromethane and the combined filtrates and washes were evaporated to dryness. The residue was dissolved in dichloromethane and the solution was washed successively with 1 mol hydrochloric acid, 1 mol saturated hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solution was filtered through charcoal and evaporated to give 2.3 g of crude trichloro product. The combined product product was determined from ethanol and found 1.4 g (67%) of crystalline 4,1 ', 6'-trichloro-4,1', 6'-trideoxy-2,3,6,3 ', 4'-penta-0-acetyl-galacroserose was obtained. Further substances can be obtained from the mother liquor.

Example 4

Chlorination using triphenylphosphine

Triphenylphosphine (13.1 g, 6 mol) at 0 ° C. in a solution of 2,3,6,3 ', 4'-penta-0-acetyl-sucrose (4.0 g, 1 molar equivalent) in pyridine (100 ml) Equivalent) followed by carbon tetrachloride (3.9 g, 3 molar equivalents). The mixture was heated to about 70 ° C. for 3 hours and then cooled. Methanol (120 ml) was added to the cooling mixture and evaporated to dryness to dissolve the residue in methylene chloride, washed successively with 1M HCl and NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered through charcoal and finally evaporated again to syrup Got. Acetone was added to the residue and the costly material was filtered out. The solution was evaporated again and the residue was determined from ether. These crystals contained no sugars, the solution was evaporated while discarded and determined from ether / petrol to give 3.4 g (60%) of trichloro sucrose penta acetate slightly contaminated with triphenylphosphine oxide. . Recrystallization gave a pure product (2.3 g, 40%)

Example 5

4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose-2,3,6,3 ', 4 from reagents derived from PCl ₅ and dimeformamide '-Penta-0-acetate

Phosphorus penta chloride (50 g, 0.24 mol) was added in small portions to DMF (140 g, 1.92 mol) while the temperature was raised to about 120 ° C. with stirring. The mixture was cooled to 0 ° C. and N, N-dimethyl-chloromethaneimium chloride was determined and filtered. (See Hepburn and Hudson, J. C. S. Perkin 1, 754, 1976). To 1,1,2-trichloroethane (120 ml) was added N, N-dimethyl-chloromethaneimium chloride (14 g, 4 molar equivalents). This mixture was added. The mixture was cooled to 0 [deg.] C. and 2,3,6,3 ', 4'-penta-0-acetylsucrose (15 g, 1 molar equivalent) was added, the combined mixture was stirred and under nitrogen atmosphere for 4 hours. It was refluxed and left to cool. The cooled reaction mixture was filtered through a pad of charcoal and washed with dichloromethane. The combined filtrate and washings were evaporated to dryness and the residue was recrystallized from ethanol to give 13.45 g (82%) trichloropentaacetate.

Example 6

Reaction of Vilsmeier Reagent Derived from Thionyl Chloride and DMF with 2,3,6,3 ', 4'-penta-0-acetylsucrose

Thionyl chloride (8.5 ml) was added to hot DMF (8.4 ml) and the mixture was evaporated in vacuo at 50 ° C. to obtain a syrup. To this was added 1,1,2-trichloro-ethane (120 ml) and the mixture was cooled to 0 ° C. Sucrose 2,3,6,3 ', 4'-pentaacetate (15 g) was added and the mixture was refluxed for 3 hours to cool, filtered through charcoal and the reddish brown filtrate was evaporated. The resulting syrup was crystallized from ethanol to give 11.8 g (72%) of slightly colored crystals. Recrystallization gave 10.9 g (70%) of almost colorless crystalline trichloro-sucrose pentaacetate.

Example 7

Preparation of 4,1 ', 6'-trichloro-4,1', 6'-trideoxygalactosucrose penta acetate using Vilsmeier reagent formed in situ

2,3,6,3 ', 6'-penta-0-acetyl sucrose (5 g, purity 80%) was dissolved in a mixture of toluene (40 ml) and dimethylformamide (8.6 ml). A solution of thionyl chloride (8.3 ml) in toluene (15 ml) was slowly added to the stirred reaction mixture while the temperature was raised to 40 ° C. for at least 15 minutes. At the end of the addition, the mixture was stirred again for 15 minutes and heated to reflux to reflux for 5-6 hours. The reaction was performed by thin layer chromatography. Charcoal was added when the reaction was complete and the warm mixture was stirred for 20 minutes and then filtered through a filter pad. The residue remaining in the flask was also washed with filtered small amount of toluene. The combined filtrate and washings were evaporated and the residue was determined from toluene (20 ml) to give 4,1 ', 6'-trichloro-4,1', 6'-trideoxy galacto sucrose penta-acetate (4.32 g, Purity 85.5%) was obtained in a yield of 84% or more.

Example 8

Reaction of Vilsmeier reagent with 2,3,6,3 ', 4'-penta-0-acetyl sucrose derived from thionyl chloride and catalytic amount of DMF

To 2,3,6,3 ', 4'-pentaacetate (2.75 g) in 1,1,2-trichloroethane (20 ml) was added DMF (about 0.15 ml) and the mixture was refluxed. Thionylchloride (1.7 ml) in 1,1,2-trichloroethane (10 ml) was added for about 45 minutes and the mixture was refluxed for another 5 hours. Again 0.15 ml of DMF and 1 ml of sulfuryl chloride were added to the mixture at once and refluxed again for 3 hours.

The black reaction mixture was filtered through charcoal and the reddish brown filtrate was evaporated to give a syrup determined from ethanol, yielding 6.3 g (40%) of trichlorosucrosepentaacetate as white crystals.

Example 9

Chlorination of Sucrose 2,3,6,3 ', 4'-Penta-0-acetate Using Triphenoxydichlorophosphoran

Chlorine gas was bubbled into triphenol phosphite (3.1 g, 2.6 ml, 4 molar equivalents) (supplied by Aldrich chemical Co. Ltd) with stirring until a weight of 0.7 g was observed. During the application of chlorine the liquid became very hot and solidified upon cooling. The cooling material was dissolved in pyridine (20 ml) and dissolved by addition of sucrose 2,3,6,3 ', 4'-penta acetate (1.4 g, 1 molar equivalent). Crystalline precipitate formed almost directly and the mixture was very warm. After 10 minutes, the sample was removed from t.l.c. A single main product (Rf 0.5) corresponding to pentaacetate of TGS with two smaller components (Rf 0.3 and 0.0) on (ether / phenol) was shown. The mixture was stirred for another 1 hour, poured into water and extracted with chloromethane. The extract was washed with 0.1N HCl and sodium hydrogen carbonate, dried (sodium sulfate), filtered through charcoal and evaporated to give a pale yellow syrup. The syrup was eluted with diethyl ether / 40 ° -60 ° petroleum ether (4: 1) and chromatographed on a silica gel column to give TGS penta acetate (1.2 g, 78%) as determined from ethanol, consistent with the true sample. I found out.

Example 10

Chlorination of sucrose 2,3,6,3 ', 4'-penta-0-acetate using triphenyl-dichlorophosphoran

Chlorine gas was bubbled at 0 ° C. with stirring until a weight of 1.4 g was observed in a triphenylphosphine (5.6 g, 8ME) solution in carbon tetrachloride (20 ml). Care must be taken not to block the inlet tube with reagents formed during the reaction. The reaction mixture was very hot and was slightly externally cooled. Sucrose penta acetate (1.4 g, IME) is added to the stirring solution to dissolve while releasing some heat. The solution was left at room temperature for 2 1/2 hours, heated to 55 ° C. for 2 hours, and then heated to 85 ° C. for 3 hours by which time the mixture darkened. tlc analysis (ether / petroleum 4: 1) showed that a single compound (Rf 0.5) was present corresponding to TGS penta acetate. The pyridine was evaporated and the residue was dissolved in dichloromethane, washed with 0.1N HCl and NaHCO ₃ solution, dried (sodium sulfate), filtered through charcoal to give a colorless filtrate and evaporated to give 6.5 g of syrup. This was chromatographed as in Example 8 to give 1.1 g of TGS penta acetate determined from ethanol in 78% yield.

Claims (1)

As described above, the isomerization step is performed by reacting a 2,3,4,3 ', 4'-penta-0-acetylsucrose solution in an inert solvent with a weak acid at an elevated temperature. Isomerized to 2,3,6,3 ', 4'-penta-0-acetylsucrose, 4,1' and 6 A process for the preparation of 4,1 ', 6'-trichloro-4,1'6'-trideoxy galactosucrose, comprising deacetylating the chlorinated product obtained by chlorination of the isomerized acetate at the' -position.