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AU593293B2 – Process for the preparation of 1,6-dichloro-1,6-dideoxy-beta -d-fructofuranosyl-4-chloro-4-deoxy-alpha-galactopyranoside
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AU593293B2 – Process for the preparation of 1,6-dichloro-1,6-dideoxy-beta -d-fructofuranosyl-4-chloro-4-deoxy-alpha-galactopyranoside
– Google Patents
Process for the preparation of 1,6-dichloro-1,6-dideoxy-beta -d-fructofuranosyl-4-chloro-4-deoxy-alpha-galactopyranoside

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AU593293B2

AU593293B2
AU64214/86A
AU6421486A
AU593293B2
AU 593293 B2
AU593293 B2
AU 593293B2
AU 64214/86 A
AU64214/86 A
AU 64214/86A
AU 6421486 A
AU6421486 A
AU 6421486A
AU 593293 B2
AU593293 B2
AU 593293B2
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Prior art keywords
penta
acetylsucrose
preparation
fructofuranosyl
dideoxy
Prior art date
1985-10-21
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AU6421486A
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William Tully
Nicholas M. Vernon
Peter A. Walsh
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Janssen Pharmaceuticals Inc

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McNeilab Inc
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1985-10-21
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1986-10-20
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1990-02-08

1986-10-20
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1987-04-30
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1990-02-08
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1990-02-08
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2006-10-20
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Classifications

A—HUMAN NECESSITIES

A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES

A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL

A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS

C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium

C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS

C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids

C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids

C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Abstract

A process for the preparation of 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-galactopyranoside comprising the steps of (a) reacting sucrose with a tritylating agent; (b) acetylating the tritylated reaction product; (c) detritylating the acetylated reaction product; (d) isomerizing the resulting penta-acetate; (e) chlorinating the isomerized product; and (f) deacetylating the chlorinated reaction product.

Description

F
-i r~ _l _i _Ll^_l.li i- _~IIIII-Y–*rYII L_-YE9I~Cb-W~Q~ ~Y*i COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 Form COMPLETE SPECIFICATION FOR OFFICE USE Short Title: Int. Cl: 614IJ Application Number: Lodged: 593293 Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: This document contains the| amendments made under Section 49 and is correct for printing. j TO BE COMPLETED BY APPLICANT *4 o#e6 i
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Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: McNEILAB, INC.
Spring Houser PA, U.S.A.
William Tully Nicholas M. Vernon and; Peter A. Walsh GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000
AUSTRALIA
Complete Specification for the invention entitled: PROCESS FOR THE PREPARATION OF 1,6-DICHLORO-1,6-DIDEOXY- -D-FRUCTOFURANOSYL-4-CHLORO-4-DEOXY-a-GALACTOPYRANOSIDE The following statement is a full description of this invention, including the best method of performing it known to me/us:- 8845A:rk PROCESS FOR THE PREPARATION OF 1,6-DICHLORO-.16-DIDEOXY- -D-FRUCTOFURANOSYL-4-CHLORO-4-DEOXY-a-GALACTOPYRANOSIDE Background of the Invention This invention relates to a process for the preparation of 1,6-dichloro-1.6-dideoxy–D-fructofuranosyl-4-chloro-4deoxy-a-galactopyranoside. This compound is a potent sweetener, having a sweetness several hundred times that of sucrose. Its use as a sweetener and in sweetening compositions is disclosed in U.S. Patent No. 4,435,440.
The preparation of 1.6-dichloro-1.6-dideoxy—D-fructofuranosyl-4-chloro-4-deoxy-a-galactopyranoside or as it is sometimes referred to in the literature. trichloro-4,1′,6′-trideoxygalactosucrose. (hereinafter ‘1 referred to as “sucralose”) involves the substitution of chlorine atoms in the sucrose molecule in one of the five secondary hydroxyl positions and in two of the three primary hydroxyl positions. This particular selection of positions usually means that any synthetic route must involve the preparation of an intermediate sucr( d derivative having the required positions available for chlorination while the other positions are blocked. In particular, the reactive 6-position must not be chlorinated, while the 4-position must be rendered available for chlorination.
One route proposed in the literature (Fairclough et al, Carbohydrate Research 40 (1975) 285-298) involves the formation of the 6,1′,6′-tritrityl derivative of sucrose, peracetylation of the molecule and then detritylation with migration of the 4-acetyl radical to the 6-position, to give 2.3,6,3.,4′-penta-O-acetylsucrose which has the MN 436 -2correct hydroxy groups unprotected. Subsequent reaction with a chlorinating agent provides the 4,1′,6′-trichlorogalactosucrose penta-acetate which in turn yields sucralose on removal of the acetyl groups. The chlorination proceeds with inversion of configuration at the 4-position. The 1′ and 6′-positions freely rotate, but the 4-position cannot and the glucose ring is thus inverted at the 4-position yielding a galactose derivative so that the product is a galactosucrose.
Another route is set forth in U.S. Patent No. 4,380,476 and comprises the steps of: reacting sucrose with an acylating reagent under conditions to provide a mixture of acylated sucrose derivatives containing a major proportion of 6-monoacylated material: optionally separating the 6-monoacylated sucrose derivative from other acylated derivatives before step reacting the monoacylated sucrose derivative with a chlorinating reagent capable of chlorinating at positions 4 and 6′ of a sucroe 6-acylate: and deacylating and separating (in either order) the sucralose material formed.
A further process for preparing sucralose is set forth in U.S. Patent No. 4.362,869. This process converts sucrose through a number of steps into sucralose. This process describes the sequential steps of tritylation of rsucrose to block the three primary alcohol groups; (2) acetylation of the five secondary alcohol groups as i acetates; detrityltion of the three primary alcohol P 30 groups to deblock them; acetyl migration from tne 4-position to the 6-position chlorinating the desired alcohol groups at positions 4, and deblocking the remaining five alcohol groups by deacetyltion thereby yielding aucralose.
MN 436 -3 The invention disclosed in U.S. Patent 4,362,869 is centered around the acetyl migration from the 4-position to the 6-position which is effected by treating a solution of 2,3.4,3′,4’-penta-O-acetyl sucrose in an inert solvent with a weak acid at an elevated temperature. It was found that selection of specific reaction conditions for the acetyl migration gave considerably higher yields overall for separate detritylation and migration than the prior art which taught a one stage process for these steps. The weak acid utilized is preferably a carboxylic acid.
especially an aliphatic carboxylic acid such as acetic acid. It is stated that any acid having an acid strength of the same order as acetic acid under the conditions used will suffice. The reaction temperature should be elevated above ambient temperature in order to provide an acceptable reaction time. A temperature of from about 0 to 150 0 C is said to be suitable, preferably 1000 to 130 0
C,
The inert solvent is said to be any solvent for penta-O-acetyl sucrose which remains liquid at the elevated temperature selected, e.g. a temperature in the range of 1000 to 140 0 C. Ketonic solvents are particularly preferred. especially methyl isobutyl ketone, wichreflxesat aout117 0 C. A dilute solution of the soluionof fom to10% by weight, especially about This degree of dilution is suitable for reaction with the sucrose penta-acetate dissolved at a concentration of up to 30% by weight. e.g. about 20%. Ester solvents of sufficiently high boiling point are also ‘Useful, e.g.
n-butyl acetate. Also of particular interest are aromatic hydrocarbons such as toluene or xylene.
When tne reaction is completed, the reaction mixcture is MN~ 436 4cooled and 2.3.6,3’4′-penta-0-acetylsucrose crystallizes.
After an additional period of time at 0 C. the crystalline product is filtered, washed and dried and then proceeds to the chlorination step. While an effective process, the above process involves the use of a carboxylic acid at high temperatures in the pres.ence of free hydroxyl groups, conditions known to promote acylation.
The prior art also reveals that dilute aqueous solutions of bases are suitable for carrying out acetyl migrations.
Although a migration occurs from the 4 to the 6 positions of the glucose ring with 0.001 N sodium hydroxide, the yield is very low due to concurrent deacetylation. When 2 to 5% solutions of a very weak base. pyridine or substituted pyridines, e.g. 2,4 and 2.6 lutidines or 2.4.6 tri-methyl pyridine (collidine) are used in water.
reasonable yields of 2.3.6.3’.4′-penta-O-acetyl sucrose are obtained, however, deacetylation and further migration to give 3.4.6,3′,4′-penta-0-acetyl sucrose also occurs.
It is an object of an embodiment of the present invention to provide an improved process for the preparation of sucralose.
It is a further object of an embodiment of the present invention to provide a process for the preparation of sucralose wherein the acetyl migration step of U.S. Patent No. 4,362,869 can be accomplished without utilizing a weak t 30 acid.
S’Broadly, the present invention lies in a process fnr the Se preparation of 2,3,6,3′,4′-penta-0-acetylsucrose comprising isomerizing 2,3,4,3′,4′-penta-O-acetylsucrc -e in a non-aqueous solvent with a weak base.
MN 436 5 An embodiment of the invention is an improved process for the preparation of sucralose. This process comprises the steps of tritylation of sucrose to block the three primary alcohol groups; acetylation of the five secondary alcohol groups as acetates; detritylation of the three primary alcohol groups to deblock them; (4) acetyl migration; selective chlorination: and (6) deacetylation to deblock the remaining alcohol groups to yield sucralose.
It has now been found that the acetyl migration can be 15 carried out utilizing a weak base catalyst in a non-aqueous solvent. These bases should be kinetically active but sterically hindered to inhibit deacetylation and minimize side reactions. Specific base catalysts which have been found useful for acetyl migrations include tert-butylamine. triethylamine, pyrrolidine.
di-N-propylamine, di-isopropylamiie. morpholine, n-butylamine, isopropylamine, pipe-idine. diethylamine and the like.
‘he reaction temperature should be from about 300C to 600C. preferably about 50 0 C. If the temperature is raised above 60 C then the risk of side reactions increases and if the temperature is kept below about the reaction may proceed too slowly. The reaction proceeds to completion in from about 2 1/2 hours to hours depending on the selected amine and temperature.
MN 436 6 The migration takes place in any inert solvent in which 2,3.4,3′,4′-penta-0-acetyl sucrose is sparingly soluble, excluding alcohols or primary and secondary amines, where potential for a base catalyzed deacetylation reaction exists. The migration takes place in the following representative solvents: toluene, tetrahydrofuran, methylene chloride, ethyl acetate, acetone, acetonitrile, pyridine (with a stronger base catalyst like tert-butylamine). The best solvents are those in which the product, being only partially soluble, crystallizes out early and drives the reaction to completion. Toluene, ethyl acetate and methyl isobutylketone are examples of this class. High amine concentrations inhibit crystallization and for his reason the catalyst level should not exceed about 8%.
A major embodiment of this invention is that the acetyl migration and chlorination reactions leading to sucralose can be carried out not only in discrete steps but also in tandem without the necessity of separating out the migrated product prior to chlorination provided are chosen: a solvent compatible to both reactions, and a base catalyst easily removed prior to chlorination.
The selected solvent should, in particular, be inert to the chlorinating Agents and hiave a boiling point high S enough to ensure complete chlorination, preferably above 30 about 80 C.
The aromatic hydrocarbons such as toluene, xylene and the like are suitable, as are ethyl acetate, methyl isobutylketone. dichloroethane and other solvents which satisfy the earlier stated requirements.
MN 436 7 As discussed above, the first step of the process involves the tritylation of sucrose to block the three primary alcohol groups. This can be accomplished by reacting sucrose with trityl chloride in a suitable solvent such as pyridine. It has also been noted that increased yields at lower costs can be achieved when the solvent is changed from pyridine to dimethylformamide wherein a tertiary N-methylmorpholine) or polymer-bound poly-2 vinylpyridine) amine is used as acid scavenger.
After completion of the reaction and the blocking of the three primary alcohols, the tritylated reaction product is subjected to in-situ peracetylation with acetic anhydride. If pyridine is used as a solvent, the reaction mixture after acetylation is poured nto ice water and the precipitated product filtered and dried. The procedure is repeated a number of times to remove any traces of pyridine and a crystallization yields 6,1′,6′-tri-O-tritylsucrose penta-acetate.
If dimethylformamide is used as the soavent during tritylation, then the N-methylmorpholine hydrochloride can be neutralized in-situ by the addition of sodium hydrogen carbonate and the solution concentrated to remove N-methylmorpholine and a large portion of the dimethyl- Sformamide. Acetic aahydride and a catalyst such as St pyridine, 4-dimethylaminopyridine or potassium acetate are added to the residue. After reaction, crystallization by S methanol a4dition affords yields 6,1’.61-tri-o-trityl- S 30 sucrose penta-acetate. Alternatively, the dimethylformamide and N-methylmorpholine are removed by extracting frojm eoluene with water and the tritritylsucrse acetylated in toluene solution.
The detritylation step can be accomplished by dissolving MN 436 -w4 *«.*mtao diinafrsyed .1 ‘ti.-rtl 8 the 6.1′,6′-tri-O-tritylsucrose penta-acetate in dichloromethane and acetic acid, cooling the solution to 0°C and adding concentrated hydrochloric acid. After stirring for two hours, the solution is neutralized.
After additional stirring and concentration, methanol is added resulting in the precipitation of triphenylmethanol. The solution is then concentrated and ether is added and 4′-penta-O-acetylsucrose is crystallized out at room temperature.
Other methods of detritylating the 6,1′,6′-tri-0-tritylsucrose penta-acetate (TRISPA) can also be utilized. For o0 o0 example, hydrogen chloride can be reacted with the penta-acetate solution in toluene at about 0 C with the S 15 2,3,4,3 ,4’-penta-O-acetylsucrose isolated by filtration 0 a and the trityl chloride ‘ecovered by concentration of the mother liquor. The detritylation can also be accomplished t in a methylene chloride solution using hydrogen chloride as the catalyst in methanol, in methylene chloride/formic acid solution by the dropwise addition of water, or in methylene chloride using a Lewis acid.
The 2,3,4,3′,4′-penta-0-acetylsucrose is then subjected to the acetyl migration as discussed above followed by chlorination of the resulting 2,3,6,3′,4′-penta-0acetylsucrose. The chlorination can be accomplished utilizing any suitable chlorinating reagent. These reagents include Vilsmeier type reagents (e.g.
dimethylformamide/thionyl chloride), triphenylphosphine/carbon tetrachloride in a suitable solvent such as methyl isobutylketone and sulphuryl chloride/pyridine; thionyl chloride/triphenylphosphine oxide or any other suitable chlorinating reagent.
The chlorination results in the formation of MN 436 9 Si
I
4,1′,6′-trichloro-4,1, 1 .6′-trideoxygalactosucrose pentaacetate. The deacetylation can be achieved with methanol and sodium methoxide to yield the desired Isucralose.
Specific embodiments of the present invention are illustrated by the following representative examples. It will be understood, however, that the invention is not confinad to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
EXAMPLE 1 t Tritylation and Acetylation Sucrose (50 g, 0.14 mol) is mixed with N-methylmorpholine g. 0.59 mol) in dimethylformamide (100mls) at 50 0
C.
trityl chloride (141.8 g of 97% purity, 0.49 mol) is added in three portions over 2.5 hours and heating continues for hours. Sodium hydrogen carbonate (42.7 g, 0.5 mol) is added and heating at 50°C continues for one hour. All solvents are removed under vacuum and the residue is dissolved in acetic anhydride (96.6 mis, 1.02 moles).
Potassium acetate (15.6 g, 0.15 moles) is added and I S, heating at 115 0 C is undertaken for 3 hours. After cooling methanol (400 mis) is added and after crystallization is complete a solid (183.2 g) was obtained which contained 6.1,6’-tri-O-tritylsucrose penta-acetate (TRISPA) (124.6 g. 68.6% yield).
MN 436 EXAMPLE II Tritylation and Acetylation Sucrose (40g, 0.11 mol) is mixed with N-methylmorpholine 0.49 mol) in dimethylformamide (120 mis) at 50 C.
trityl chloride (95 g of 97% purity, 0.33 mol) dissolved in hot (60 C) toluene (60 mis) is added in three portions over the same number of hours. Heating is continued for three further hours after which toluene (140 mis) is added. The mixture is extracted with 50 ml portiJns of brine at 60°C (to prevent emulsions forming). On complete removal of the N-methylmorpholine ,o hydrochloride and the dimethylformamide the 15 toluene/tritrityl sucrose is dried by azeotroping off the I water. Acetylation with acetic anhydride (75 mis, 0.8 mol) and pyridine (5 mis) at 90°C for 3 hours is followed by cooling and crystallization with methanol (420 mis) yielding as solid (112.7 The TRISPA content was 91.4% (103 g) implying a 68.9% yield.
EXAMPLE III Tritylation and Acetylation To an agitated mixture at 400C of sucrose (50 g, 0.146 mol), dimethylformeide (100 ml) and dry activated poly-2-vinylpyridine (63 g, 0.53 mole eqvivalents) was added in three charges trityl chloride (3 x 44.7 g) at hourly intervals. The mixture, held at 40°C for a further 12 hours, was filtered free of the polymer, washiag the filter cake successively with hot methylene chloride and acetone. The combined filtrate and washings were evaporated to dryness under vacuum. To the viscous MN 436 residue (206.7 1.1 viol) and 4resultant solut the cool.ed mixt TRISPA (11,8 g filtered in a y 11 g) was added =cetic anhydride (11(.5 g.
*dimethylaminopyridine (3 g and the ~ion was agitated at 80%1 f or 2 hours. To ure was added methanol (200 ml) and the slightly contaminated with tritanol, was ‘ield of 53.7%.
EXAMPLE IV Detritylation o *AAO 0 004044 4 4 44 4 44 4 44
I
TRISPA (200g) is dissolved in toluene (800 ml) and the solution is cooled to 0 0C. Hydrogen chloride, gas 15 (i7.1g) is passed into the cooled stirred solution over hours. after which the slurry of precipitated 2. 3 .4.3 1,4 1 -enta-0-acetyl sucrose (4-PAS) is stirred for mins. The system is purged with nitrogeza under vacuum for 1 hour, to remove residual hydrogen chloride. The resultant mix.*ure is filter~ed and washed w..th toluene mls), granulated and reslurried in toluene containing 1’% triethylamine (120 mls) for 10 mins. The mixture is again filtered, washed with toluene (65 ml) and dried and yields 87g corrected for assgay) of 2,3,4,3′ .4-penta-0-acetylsucrose The mother liquor is concentrated to dryness giving crude trityl chloride (135g. 95%, correcied for assays).
EXAMPLE V Detritylation TRISPA (50g) is dillsolved in CH 2Cl 150 mls. Methanol (15 myl, contalninj HCl 0.2 equivalents) 18 added MU 436 r -12 and the solution is stirred at room temperature for hours. The HC1 is neutralized with tertiary butyl amine (1 ml). The CH Cl 2 and methanol are evaporated at room temperature under vacuum, leaving a solid. The solid is slurried in methanol (120 ml) for 30 minutes, water (6 ml) is added and stirring is continued for 10 minutes.
The tritylmethylether is filtered (28.4g) and washed with a solution of water (2ml) in methanol (48ml). The filtrate is reduced to an oil under reduced pressure and ethyl acetate (100ml) is added to azeotrope off any residual water. The oil was dried overnight at 400C under vacuum. The resulting product weighed 26.4g, yield a.o 58.2% correcting for assays.
o 0 0 o EXAMPLE VI Detxitylation TRISPA (25g) was dissolved in methylene chloride (87ml) at room temperature and formic acid (87 ml, 95%) added.
Water (11 ml) was added to the stirred solution over a minute period. After stirring for a further 5 mins the reaction was quenched by addition of water (100 ml) and 2I the triphenyl methanol was filtered and washed with water (100 ml) and the filtrate and wash were combined, neutralized to pH 6.5 by addition of solid sodium carbonate and extracted with methylene chloride (1 x 100ml, 2 x 25m). Concentration of the extracts gave 4-PAS as an oil in 79% yield. The triphonyl methinol yield was 15.4g, 100%.
MN 436 13 EXAMPLE VII Detritylation TRISPA (25g) was dissolved in methylene chloride Aluminium trichioride (110.5g) was added. The solution became warm and was stirred for one hour. Water (90m1) was added. The layers were separated leaving the aluminium trichloride in the aqueous layer. Water (lO0ml) was added and the methylene chloride evaporatad under reduced pressure at ambient. The precipitated tritanol was filtered and the water extracted with CH 2Cl 2′ The CH 2Cl awas evaporated to give 2. 3,4,31 4 1 -penta-O-acetylsucrose (YielId 6g, EXAMP LE VIII Agetyl Migration and Chlorinatiorn 4-PAS (150g,) is dissolved in methylisobutylketone and heated at So0 0 C for 5 hours with tert-butylamine The solution is concentrated to 600ml in. vacuo at 60 0 C and, triphenyl phosphine (336..5g) and carbon tetrachloride (69.3m1) are added. On heating to 60 0 C an exotherm occurs raising the temperature to 100C. The mixture is refluxed for 1 hour, t~cooled to 50 0 C and water (38.5m!) and sodium b! car bona~- (25.7g) are added.
After cooling to 0 0 C wivth agitation. the precipitated triphenylphosphine oxide is separated by filtration and washed with %jold methyl isobutylkr~tode (100ml). The combined filtrate and washings are concontrated to dryness. the residue being dissolved in alcohol (500m1) and cooled to 0 0 C. The crystallized 4,l’,64-trichloro- 4,10.6′-trideoxygalactosucrose penta-acetate (TOSPA) was MN 436
U
14 isolated by filtration and dried. (88.0g 60%, correcting I for assays).
EXAMPLE IX Acetyl Migration and Chlorination 4-PAS (50q) is dissolved in pyridine (300ml) and heated at 50 0 C for 4 hours with tert-butylamine (5ml). 50ml of pyridine is removed by vacuum distillation and the residue is cooled to -20°C. Sulphuryl chloride (25.5ml) was «added at a rate to keep the temperature below 10 C.
Addition took 1 hour. The solution was rapidly heated to 100C for 1 min and then rapidly cooled. The pyridine was distilled off in vacuo at 50°C to leave an oil (lO0mls) which was poured into water with rapid stirring.
The solid was collected by filtration and recrystallized from methanol to give TOSPA (23g, 47% yield corrected for assays).
EXAMPLE X Acetyl Migration 4-PAS (200g) is mixed with ethy’acetate (322mls), heptane 28mls) and tert-butylamine (21 mls) at 50°C for hours. 6-PAS is observed to crystallize during the reaction but complete crystallization is obtained by the addition of heptane (124 mis) at the reaction temperature followed by cooling and stirring for 3 hours. After filtration and washing of the cake with a mixture of ethylacetate-heptane (100 mls) it is dried in a vacuum oven at 40°C for 16 hours. A white solid (140.3g) MN 436 15 containing 85.4% 6-PAS (1.19.8g) is obtained. Yield 85.4%.
EXAMPLE XI Chlorination To a slurry of 2,3,6,3′.4′-penta-0-acetyl sucrose (59g.
90.4 mmol.) and triphenylphosphine oxide (125.8 g, 454 mmol.) in 1,2-dichloroethane was added thionyl chloride (32.8 ml. 452 mmol.) at ambient and the mixture heated to reflux for 3 hours. Sodium bicarbonate (20 g) in 220 ml of water were added slowly and the biphasic mixture agitate for .5 hour. The organic layer was separated.
evaporated to dryness under vacuum and methyl isobutyl ketone (150 ml) added. On cooling at 0 C for 1 hiour, triphenylphosphine oxide (ca. 98g) separated and was isolated by filtration, washing the filter cake with methyl isobutyl ketone (50 ml). The mother liquor was evaporated to dryness under reduced pressure and the residue recrystallized from ethanol, giving 4.1′.6 trichloro-4,1′,6′-trideoxy-2,3.63′ ,4-penta-O-acetylgalactosucrose (97.1 slightly contaminated with triphenylphosphine oxide.
EXAMPLE XII Chlorination To a slurry of 6-PAS (50 g) and triphenylphosphine sulphide (53.3 g) in xylene (150 ml) was added thionyl chloride (32.8 ml) and the mixture was heated at 1150C for 4.5 hr. Water (300 ml) was added and the biphasic mixture was vigorously stirred at 0 0 C for 1 hr. The MN 436 16 16 crude TOSPA was isolated by filtration and recrystallization from hot methanol (Yield 31.8 g, 66% corrected for assays).
EXAMPLE XIII De-Acetylation TOSPA (50g) is stirred at ambient with sodium methoxide in methanol (125ml) for 1.5 hours under vacull Heat is applied to maintain a temperature of 18-20 0
C.
TOSPA dissolves within 10 mins. The solution is neutralized by stirring with Amberlite IRC 50 (H resin (7.5g) to, pH 7 7.5. The resin is removed by filtration and washed with metihanol (25ml). the filtrate and wash then beiag stirred with decolorizing charcoal (4g) for mins. The solution is clarified by filtrate and concentrated to a residue in vacuo. The sucralose is crystallized from ethyl acetate (100ml), filtered, washed with ethyl acetate (25mls) and dried in vacuo at 400C for 12 hours. Yield 26g, 92% correcting for assays.
MN 436

Claims (5)

1. In a process for the preparation of 1,6 dichloro-1, 6-dideoxy-fr-D-fructofuranosyl-4-chloro-4-deoxcy- 4 -galactopyranoside comprising the steps of: reacting sucrose with a tritylating agent; acetylating the tritylated reaction product with an acetylating agent to obtain 6,l’,6′-tri-O-tritylsucrose penta-acetate; detritylating the 6,1′,6′-tri-O-tritylsucrose penta-acetate to obtain 2,3,4,3′,4′-penta-O-acetylsucrose; isomerizing the 2,3,4,3′,4′-penta-O-acetylsucrose to obtain 2,3,6,3’4′-penta-O-acetylsucrose; chlorinating 2,3,6,31,4′-penta-O-acetylsucrose to obtain 4,1′,61-trichloro-4,1′,6′-trideoxygalactosucro~e pentaacetate; and (f)d-,acetylating the chlorinated product; the improvement comprising effecting the isomerization step in a non-aqueous solvent with a weak base at a temperature of from about 30 ‘sC, to 600~C.

2. A process according to claim 1 wherein the weak base is selected from the group consisting of tert-butylamine, triethylamine, pyrrolidine, di-N-propylamine, di-isopropylamine, morpholine, n-butylamine, isopropylamine, piperidine and diethylamine.

3. A process according to claim 2 wherein the weak base is tert-butylamine.

4. A process according to claim IL wher~ein the isomerization step is carried out at a temperature of about C. by st 5 2, 1 4- 440* S *440 4 004444 p *0 4 P 4* ,4 4 *450 44 4 4 4041 ‘.11 rKI -18- A process according to claim 1, further improved by effecting the isomerization step and chlorination step without the necessity to seperate the 2,3,6,3′,4′-penta-O-acetylsucrose before chlorination.

6. A process for the preparation of 1,6-dichloro-1,6-dideoxy-B-D-fructofuranosyl-4-chloro- 4-deoxy-Jo-galactopyranoside substantially as herein described with reference to the Examples. 0G @4S4a S 4*40 Sr~ DATED this 9th day of November 1989 MCNEILAB, INC. By their Patent Attorney GRIFFITH HACK CO

AU64214/86A
1985-10-21
1986-10-20
Process for the preparation of 1,6-dichloro-1,6-dideoxy-beta -d-fructofuranosyl-4-chloro-4-deoxy-alpha-galactopyranoside

Expired

AU593293B2
(en)

Applications Claiming Priority (2)

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GB8525953

1985-10-21

GB858525953A

GB8525953D0
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1985-10-21
1985-10-21
Preparation of galactopyranoside

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AU6421486A

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1987-04-30

AU593293B2
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1990-02-08

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1985-10-21
1986-10-20
Process for the preparation of 1,6-dichloro-1,6-dideoxy-beta -d-fructofuranosyl-4-chloro-4-deoxy-alpha-galactopyranoside

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ATE84791T1
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1985-10-21
GB
GB858525953A
patent/GB8525953D0/en
active
Pending

1986

1986-10-20
IE
IE276386A
patent/IE59559B1/en
not_active
IP Right Cessation

1986-10-20
GB
GB8625107A
patent/GB2182038B/en
not_active
Expired

1986-10-20
PT
PT83581A
patent/PT83581B/en
not_active
IP Right Cessation

1986-10-20
DE
DE8686308120T
patent/DE3687564T2/en
not_active
Expired – Lifetime

1986-10-20
AU
AU64214/86A
patent/AU593293B2/en
not_active
Expired

1986-10-20
NO
NO864190A
patent/NO167033C/en
unknown

1986-10-20
DK
DK503286A
patent/DK503286A/en
not_active
Application Discontinuation

1986-10-20
JP
JP61247656A
patent/JPH0830074B2/en
not_active
Expired – Lifetime

1986-10-20
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FI864237A
patent/FI83783C/en
not_active
IP Right Cessation

1986-10-20
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ZA867949A
patent/ZA867949B/en
unknown

1986-10-20
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MX004086A
patent/MX168351B/en
unknown

1986-10-20
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SU864028397A
patent/RU1771476C/en
active

1986-10-20
US
US06/921,285
patent/US4801700A/en
not_active
Expired – Lifetime

1986-10-20
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KR1019860008785A
patent/KR940000484B1/en
not_active
IP Right Cessation

1986-10-20
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CA000520914A
patent/CA1273918A/en
not_active
Expired – Lifetime

1986-10-20
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NZ218010A
patent/NZ218010A/en
unknown

1986-10-20
EP
EP86308120A
patent/EP0220907B1/en
not_active
Expired – Lifetime

1986-10-20
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ES86308120T
patent/ES2044837T3/en
not_active
Expired – Lifetime

1986-10-20
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IL80371A
patent/IL80371A/en
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AU6421386A
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1985-10-21
1987-04-30
Mcneilab, Inc.
Chlorination of carbohydrates and other alcohols

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1987-04-22

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1987-04-22

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1991-05-15

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(en)

1986-10-20

EP0220907B1
(en)

1993-01-20

FI864237A0
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1986-10-20

PT83581A
(en)

1986-11-01

IE862763L
(en)

1987-04-21

CA1273918A
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1990-09-11

RU1771476C
(en)

1992-10-23

NO167033B
(en)

1991-06-17

IL80371A
(en)

1990-12-23

KR870003718A
(en)

1987-05-04

NO167033C
(en)

1991-09-25

PT83581B
(en)

1989-05-31

JPH0830074B2
(en)

1996-03-27

EP0220907A2
(en)

1987-05-06

KR940000484B1
(en)

1994-01-21

ZA867949B
(en)

1988-05-25

GB8625107D0
(en)

1986-11-26

ATE84791T1
(en)

1993-02-15

ES2044837T3
(en)

1994-01-16

GB2182038A
(en)

1987-05-07

US4801700A
(en)

1989-01-31

IL80371A0
(en)

1987-01-30

GB2182038B
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1989-09-20

DE3687564D1
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1993-03-04

AU6421486A
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1987-04-30

NZ218010A
(en)

1988-11-29

MX168351B
(en)

1993-05-19

FI864237A
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1987-04-22

EP0220907A3
(en)

1988-12-07

FI83783C
(en)

1991-08-26

GB8525953D0
(en)

1985-11-27

IE59559B1
(en)

1994-03-09

NO864190D0
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1986-10-20

JPS62155289A
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1987-07-10

DE3687564T2
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1993-07-15

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