Note: Descriptions are shown in the official language in which they were submitted.
~ ` 1076~f~f
- `, This invention relates tc sweeteners for ingestible products,
oral compositions and r,weetening compositions.
", ,
, ~ By an "ingestible product" there is meant one which in the
., : -
ordinary course of use is intended to be swallowed, for instance a
foodstuff or beverage, or an orally administered pharmaceutical
` composition. By an "oral composition" there is meant one which in the
ordinary course of use is not intended to be ingested as such, but is
taken into the mouth for the treatment of the throat or buccal cavity,
:` . :''
for instance a toothpaste, tooth powder, mouth wash, gargle, troche,
dental lotion or chewing gum. By a "s
weetening composition" there
is meant a composition which is not itself taken orally, elther to be
` ~ ~ ingested or held in the mouth, but instead is intended to be added to
. other ingestible products or oral compositions to render them sweet
- or to increase their sweetness.
Although sucrose is still the most widely used sweetening
agent, many efforts have been made to find substantially sweeter
I alternatives which could be used when it is desired to combine a high
` degree of sweetness with a low calorie content and/or a lo~1v risk of
dental caries, for example in dietetic products and in the manufacture
of soft drinks. The two most sùccessful non-sucrose sweeteners (that
is to say sweeteners comprising a compound other than sucrose itself)
~ 1
' f ~ to date have been saccharin and cyclamate, having respectively about
;, 200 and about 30 times the sweetening power of sucrose, but the use
~' of these sweeteners, particularly c;srclamate, has recently been
~:, . (1) '
'` . ~
''`'1 ' ' :'
. .
. : . . , ~ . . . .... : . , ,.
.. . . ~ .... . . .
76~0
- ~ restricted or banned in some countries because of doubts about their
safety. Saccharin also suffers from the disadvantage of an unpleasantly
bitter after-taste which can be detected by rnany people.
:, i :.,
More recently, many other non-sucrose sweeteners have been
~, 5 investigated, some of natural origin and others synthetic, covering a
wide range of chemical structures. These compounds have included
proteins, such as monellin, thaumatin and miraculin, dipeptides such
as aspartame, and dihydrochalcones such as neohesperidin dihydro-
~; chalcone. However, apart from the difficulties of synthesizing orextracting such sweeteners, they do not necessarily possess the same
quality of sweetness as sucrose: in particular, as compared with
sucrose, the sweetness may be ilow in onset and relatively lingering,
and there may be a liquorice-like or other after-taste, making the
. . ~ .
sweetener unsuitable as a direct replacement for sucrose unless these
differences can be masked.
Although numerous sweeteners of widely diverse chemical
structures have now been investigated, it is significant to note that
.. i~ ~ - .
sweetness substantially greater than that of sucrose has not been
; ~ . .
discovered in any derivative of sucrose or in any other carbohydrate:
when an intensely sweet substance has been discovered, such as
saccharin, cyclamate and the other non-sucrose sweeteners already
.
mentioned, its structure has always been radically different from that
of sucrose, Indeed, it is known that the presence of some substituents
: .
on the sucrose molecule can, in fact, destroy its sweetness and even
(2)
~-,
:' .
. . . ,.: . ,,,,.. . ,. , ~,,. , : . . . . . . .
1 () 7 6 ~ 10
impart a bitter taste.
,, :, -.
Most surprisingly, and in complete contrast to previous
, i . -
knowledge about non-sucrose sweeteners, we have now discovered
that certain derivatives of sucrose and of a sucrose isomer are
very much sweeter than sucrose itself, their sweetness being : -
; comparable in intensity with that of saccharin, but having a ~ : :
~ j . .. .
quality similar to that of sucrose.
. According to the present invention we provide as .~ ~
sweetening agents sucrose derivatives of the general formula: - .-
.-; :
` lo R3 R~
~ ~o~ S ~
1 OH ` -
:. , ,
i - in which Rl represents a hydroxy group or`a chlorine atom; R2
~ and R3 respectively represent a hydroxy group and a hydrogen
:`1. : atom, a chlorine atom and a hydrogen atom, or a hydrogen atom
~ and a chlorine atom, the 4-position being in the D-configuration; .
R represents a hydroxy group; or, if at least two of Rl, R ,
R3 and R5 represent chlorine atoms, R4 represents a hydroxy
¦:~: group or a chlorine atom; and
.,( . .:: .
,.~ ,. . .
. -
. ,' I , .
~:.: .
., ~ ,.: .
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~i 30
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: ~. ,
,..................................................................... ... ..
--3~
. , . , . . . . - . , : .
. : :,': ,- ' . ,' ' ' . ' ~ . : ' '.
.: ' ''.. .,, ., ": ': ., ' ' ,: ', ' ' ' ' .: ' , . .. . . . .
,.,. . ,: . . , . , .. ,, , :
~ ` 10761~0
R represents a hydroxy group or a chlorine atom; provided that
~-: at least one of Rl, R2 and R3 represents a chlorine atom; with
the exception of 4-chloro-4-deoxy-~-D-galactopyranosyl-~-D-
. fluctofuranoside, 4-chloro-4-deoxy-~-D-galactopyranosyi-1,6-
: dichloro-1,6-dideoxy-~-D-fructofuranoside,4,6-dichloro-4,6- .
dideoxy-~-D-galactopyranosyl-6-chloro-6-deoxy-~-D-fructofurano-
side and 6,1',6'-trichloro-6,1',6'-trideoxysucrose.
~ The compounds of formula (I) can be used as sweetening
agents in any conventional way, including the sweetening of -
`: 10 "ingestible products" (as previously defined), for example ~ :
foodstuffs, beverages and orally admlnistered pharmaceutical
. ~ compositions, and of "oral compositions" (as previously defined),
for example toothpastes, chewing gums and mouth washes. They
can also be used, with.conventional liquid or solid extenders
~ and carriers, in "sweetening compositions" (as previously
.~ defined).
~: . The extender or carrier comprlses any suitable vehicle .-.
f for the sucrose derivative of the general formula (I) so that it .. : . .
can be formulated in a composition which can conveniently be
used for sweetening other products, for example granules, tablets ~ . .
or drops. The extenderor carrier may thus include, for example, ..
. conventional water-dispersible tabletting ingredients, such :
as starch, lactose and sucrose itself- low-density bulking agents . . ..
I to provide a granular sweetening composition having a volume
. per unit sweetness equivalent to that of sucrose, for example, .
I . - . . : .
spray dried maltodextrins; and aqueous solutions containing
~ adjuvants such as stabilising agents, colouring agents and
` viscosity-adjusting agents. :
',` , :
~4~ :
.. . .. . . ,, ............. . . . . , ~, .
''' ".' " '',''''"' "',,.".' ''.',' '."": ' ',.' ,'. ',' ' ' ~''',... ' , .: .'
76~0
`. .
.. :
Beverages, such as soft drinks, containing a sucrose
derivative of the general formula (I) may be formulated either as
,:
, sugar-free dietetic products, or "sugar-reduced" products containing
the minimum amount of sugar required by law. In the absence of
sugar it is desirable to add further agents to provide a "mouth feel"
;~ similar to that provided by sugar, for example pectin or a vegetable gum.
~:' '
For example, pectin may be added at a level of from 0.1 to 0.15% in a
. . i .
bottling syrup.
' i :
A number of compounds of the general formula (I) which may
'` 1 .
~ 10 be used according to the present invention are shown in the following
,
-; Table.
`:i
Table
, . ;, ~ : :
``` 1 ~ ~
.., .-
.; R3 /6R~
, ~ R2~ <~ r
: ' ml .
un
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. ~ :
j !, . 1~ ' ' '
~.'~ . ' . .
.: ' .
. ,~. ~ '" .
,~, ' ,
(5)
A~'~ , '.
:
.
.. . .
, ~ , .
~ . . . . . .
' ' ~ .
~l07~ 0
.. ... . .
Compound No, Rl R2 1~3 R4 R5 Approximate
. ~
; . 1 ClOH H OH OH 20
~ t 2 OH H Cl OH OM 5
., 3 Cl H Cl OH OH - 600 .
. 4 ClOH H OH Cl 500 :
~' 5 Cl H Cl OH Cl 2000
6 OH H Cl Cl Cl 4
,
. .t ~ 7 ClOH H Cl Cl 100
8 ClH ClCl Cl 2 00
9 ClCl H Cl Cl~ 100
",
, 1 :
54t ~ ~: * Sweetness Evaluation
., The sweetness is evaluated in aqueous solution, by comparisonwith a 10% by weight aqueous solution of sucrose. The results were
15~ ~ obtained from a small taste panel and are, therefore, not statistically
accurate, but indicate the approximate order of sweetness.
( ,, :
,, , ' ~ .
"
;~. (6)
~ ' ' '
1at761~0
The compounds in Tahle 1 are as îollows (the systematic
nomenclature is given first, followed by a trivial name based on
"galactosucrose" in those cases where a 4-chloro substituent is present):
1. l'-chloro-l'-deoxysucrose
^~ 5 2. 4-chloro-4-deoxy-~-D-galactopyranosyl-~-D-
fructofuranoside [i. e. 4-chloro-4-deoxygalactosucrose]
3. 4-chloro-4-deoxy-~-D galactopyranosyl-l-chloro-l-
.: ~
deoxy-,~-D-fructofuranoside [i. e. 4,1~-dichloro-4, 1'-
``~ dideoxygalactosucrose]
:
4. 1', 6'-dichloro-1', 6'-dideoxysucrose
5. 4-chloro-4-deoxy-~-D-galactopyranosyl-1, 6-dichloro-
1, 6-dideoxy-,8-D-fructofuranoside li. e. 4,1', 6' -tri-
~, chloro-4, 1', 6'-trideoxygalactosucrose]
6. 4, 6-dichloro-i, 6-dideoxy-~-D-galactopyranosyl-6-
15~ chloro-6-deoxy-,B-D-fructofuranoside [i. e. 4, 6, 6' -
trichloro-4, 6, 6' -trideoxy~_sucrose]
`~0~ 7, 6, 1', 6'-trichloro-6, 1', 6'-trideoxysucrose
8, 4, 6-dichloro-4, 6-dideoxy-a-D-galactopyranosyl-1, 6-
dichloro-1,~6-didsoxy-,B-D-fructofuranoside
[i, e. 4, 6, 1', 6' -tetrachloro-4, 6, 1', 6'-tetradeoxy-
~, .
alactosucrose]
` ~ ~; 9. 4, 6,1', 6' -tetrachloro-4, 6,1', 6' -tetradeoxysucrose.
~. : ::
:, :
From Table 1 it may be seen that chloro substituents at the
4-, 1'- and 6'- positions are effective in inducing sweetness. A
combination of two such substituents is synergistic and in general raises
, .
(7)
.'. - . ' '
.. 'I . , i
:: . ..... . . .. .
:` - : . ' ' ., . . . ' ~:
.,: :~ , . . . .
`` I :10761~L0
,: .
.. . .
... .
.. ~ ~ . ...
` ~` the sweetness by approximately one order of magnitude rather than
being simply additive. Thus, for example, a l'-chloro substituent by
itself gives a sweetness of 20x and a 4~-chloro substituent by itself
a sweetness of 4x, However, a 4, l'-dichloro combination gives a
; 'I .
sweetness of 600x and a 1', 6'-dichloro combination gives a sweetness
of 500x. Similarly, a combination of all three chloro substituents raises -
i, : .
~ 1 l;he sweetness by approximately one more order, the 4,1', 6'-trichloro
.... . ~ .
derivative having a sweetness of 2000x. (All sweetnesses expressed as
,: ~
- ~ multiples of that of sucrose).
',~-j: ~ ' '
In contrast, a 6-chloro substituent is disadvantageous, and ~ -
. . ., ~,
causes a reduction in sweetness by antagonising the action of the other
substituents. For this reason, a 6-chloro substituent - R in formula
may only be present when at least two other chloro substituents
are present.
In general, the 6-chloro-substituted compounds are not
., .
preferred for this reason - the most sweet compounds containing
-~ 4,1'- and 6'-chloro substituents.
. . .
The remarkable sweetness of the compounds of formula (I)
: ~ :
:~ is combined with an LD50 (lethal dose 50%) which, in the case of
compound 5 in Table 1, for example, is in excess of 16g/kg in mice,
that being the largest dose which can be administered in practice.
, 1
... .
~ Most of the compounds of the general formula (I) are known
..
~ . - (8)
i
., j
. . . .
.. . .
. . .
. .
,~ j ~076~ o
; l and can be prepared by the synthetic routes disclosed in the chemicai
; ' literature. However, none of the known compounds has previously been
recognised as possessing any useful sweetness.
~,:
Thus, Compound 5 is reported in Carbohyd, Res,, 40, (1975),
285, Compound 6 in Carbohyd. Res., 44, (1975), 37; and Compound 7
~ , ; I . .
' in Carbohyd. Res., 25, (1972), 504 and ibid 44, (1975), 12-13.
,; Compound 2 is reported in Carbohyd. Res., 40, (1975), 285-298.
., O
"
.~
.~ . i : .
,'`"`'~.: '
All of the compounds of the general formula (I), both new and
old, may be prepared by reaction of a sucrose ester, having free
hydroxy groups in the portions required to be chlorinated, with
sulphuryl chloride to obtam the corresponding chlorosulphate derlvative.
This, on treatment with a source of chloride ions such as lithium
chloride, in an amide solvent such as hexamethyl phosphoric triamide,
yields the chlorinated sucrose ester. Hydrolysis of the chloro-ester,
.
e. g. using sodium methoxide in dry methanol, then liberates the free
chlorosucrose. The reaction with sulphuryl chloride is conveniently
. . ~ ~ ,.
effected at a reduced temperature in an inert solvent in the presence of
il
, a base, for example chloroform containing pyridine.
, : .
!
A similar method can be used for further chlorinating an
already chlorinated sucrose derivative.
. .
,:', (9)
. . ~ .
." ,, .
.:. ~ , .
10~76~
,
`" 1 In general 4-chloro-sucrose derivatives can be obtained by
, reaction of the 4-chloro-~lactosucrose analogue with a souree of
'', ehloride ions at an elevated -temperature, e. g. 100-lS0 C, preferably "
', in the presence of a eatalytic amount of iodine.
. .
~' ! 5 ~The following Examples illustrate the invention further ;;
' (temperatures are given in degrees centigrade). '
, .
.~ .
! ,`' ., ' .
,~ , . .
xample 1 ' ~
. . ~ . ,:
l'~ehloro-l'-deoxysucrose (Compound 1)
a) l'-'ehloro-l''-deoxysucrose hepta~-acetate
.I ~ ----------___________ ______
A solution of 2, 3, 4, 6, 3', 4', 6' -hepta-O-acetylsucrose (2g)
~, ' in a mixture of pyridine (lû ml) and ehloroform (30 ml) was treaied with
. ~ :
sulphuryl ehloride (2 ml) at -75 for 45 minutes. The reaction mixture
was taken up in iee-eold sulphurie aeid (10%, 200 ml) and diehloro-
~, ~ methane (200 ml) and shaken vigorously. The prganic layer was then
:, , :, -
' 15 suecessively washed with water, aqueous sodium hydrogen earbonate
and water, and then dried (Na2SO4). The solution was concentrated and
~ ... .
: then extraeted with ether. The insoluble material was filtered off and
the filtrate eoneentrated to give the eorresponding l'-ehlorosulphate
derivative ( 2, 1 g)
,,; '.
. . ' .
~, 20 This syrupy residue (2g) was then treated with lithium ''
:,......................................................................... .
ehloride (2g) in hexamethyl phosphoric triamide (HMPA) (10 ml) at 90
for 24 hours. The reaction mixture was poured into iee-water, and the
, t .
' preeipitate formed was eolleeted, washed with water, and taken up in
~, (10)
.:-'- - ' '
.
:. ~ . ..... ..
.~ . ,
.
761~L0
:
ether, The organic layer was dried over sodium sulphate,concentrated
and eluted from a silica gel column with ether - light petroleum (1:1)
; . ,
to give the l'-chloro hepta-acetate as an amorphous powder
[alD + 55. 0 tc 1.2, CHC13); n.m, r. data: r 4, 29 ~d, Jl 2 3. 5Hz, H-l);
5.11 (dd, J2 3 10, OHz, H-2); 4. 56 (t, J3 4 9. 5Hz, H 3); 4. 94 (_, J4 5
Z~ H~4); 4- 32 (d~ J8~ 4~ 6. ~Hz~ H-3'); 4~ 60 (t, J4, 5, 6, 5Hz, H-4~)
7. 84-8, 01 (7 Ac). Mass spectral data: [(a) indicates ions due to hexa-
i pyranosyl cation and (b) a 3 :1 doublet (lCl) due to ketofuranosyl]:
~' ~' m/e 331 a, 307 b, 187 b, 169 a, 145 b, 109 a.
Analysis calculated for C26E35C1017 : C, 47, 7; H, 5. 4; Cl, 5. 4%
Found : C, 47. 5; H, 5, 6; Cl, 5. 7%-
:~: :
. j:~ `: : ~
(b) l'-chloro-l'-deoxysucrose
_______ .
A solution of the abo~e intermediate (lg) in dry methanol
:j :
(10 ml) was treated with a catalytic amount of M sodium methoxide in
- 15 methanol at rc,om temperature for 5 hours. T.l. c. (dichloromethane - -
methanolj 3 :1) showed a slow-moving product, The solution was
~ 7 a ~ e~Rr~ ~y
L~` j deionized by shaking with Amberlyst - 15 ~ polystyrene sulphonic acid
resin), in H form, concentrated, and purified by shaking an aqueous
.~ ~
. . ~ :
solution of the syrup with petrol. The aqueous layer was then concen-
trated and dried under vacuum to give l'-chloro-l'-deoxysucrose
. ~ .
]D ~ 57. 8 (C 0. 7, water).
,- . , : . . .
calculated for C12H21ClOlo : C~ 39- 9; ~I~ 5- 9; Cl~ 9~ 8%
Found : C, 39. 7; H, 6.1; Cl, 9. 7%.
.
:~ ! -
., (11),
.j.', , .
,
.: `
': ' ' '~ ,: ' ~ ' ' ,.
.. .
7~,1Lo
~'~, Example 2
i ~,
; . 4,1'-dichloro-4, l'-dideoxygalactosucrose (Compound 33
.- ~
(a) 2, 3, 6-Tri-O-acetyl 4-chloro-4-_eoxy-~-D-~alactopyranos~ -3, 4-
d_-O-_ce_yl-6-O-_enzoyl-l-chloro-l_deoxysucrose
A solution of 2, 3, 6, 3', 4' -penta-O-acetyl-6' -O-benzoylsucrose
I (2g) in a mixture of pyridine~ (10 ml) and chloroform (30 ml) was treated :
`~ with sulphuryl chloride (2 ml) at -75 for 45 mmutes. The reaction
mixture was poured into ice-cold sulphuric acid (10%, 200 rnl) with
vigorous shaking and then extracted with dichloromethane. The organic
1 ayer was washed successively with water, ~aqueous sodium hydrbgen
carbonate, and water, and dried (Na2SO4).~ The solution was concen-
trated~ and extracted with ether.~ The Insoluble material was filtered off
and the filtrate concentrated to~give the chlorosulphate (2, lg), This
intermediate was then treated with lithium chloride as in Example 1 to
l5~; ~glve the above-named chloro intermedlate.
(b) ~ 4-chloro-4-de xy~ D-alactop~ranos~ chloro-l-deoxy~
D - f r u c t o f u r an o s_d e
A ~solution of the above intermediate from (a) (lg) in dry
methanol was treated with a catalytic amount of M sodlum methoxide
20~ m methanol at room temperature for S hours. T. 1. c. (dichloromethane - ~,
methanol, 4 :1) showed one product. The reaction was worked up as
::,
described in Example l(b) to give the title product as a syrup,
[~]D + 49 6 (c 0. 7, water),
, Analysis calculated for C12H20C12Og : C, 38, 0; H, 5. 3; Cl, 18, 7%
Found : C, 35.7; H, 6. 0; C1,20.4%.
' '
(12)
." . ,
;.. : .
~ ` ~
10761.~0
., .
" ,
~,
By a similar method 1', 6'~dichloro-1', 6l-dideoxysucrose
(Compound 4) was prepared:
.~ I [~3D + 67 (c 1. 0, methanol),
~, ,
Analysis calculated for C12H20C1209 : C, 38, 0; H, 5, 3; Cl, 18. 7%
Found : C, 37. 7; H, 5, 2; Cl, 17,1%,
~''' 1 , .
i ~ ~ Hexa-acetate - white solid foam, [~D + 51. 7 (c 1, 0, CHCI3)
Mass spectrometry m/e 331 and 283 (2 Cl). Characterized by reductive
dehalogenation with :R.aney Nickel, H2 and KOH to l', 6'-dideoxysucrose
;~ hexaacetate - a thick colourless syrup; [~Y]D + 25. S (c 1, 0, CHC13).
100 Hz N, M. R. (C6D6 ~ values) - H-l, 4, 36 d (Jl 2 3 5 Hz); H-2,
j ~ ~ 4 99 q (J2 3 10, 5 Hz); H-3, 4,17 t (J3 4 10, 0 H2); H-4, 4. 71 t
(J4 5 l O. 0 Hz); H-l ', 8, 58 s; H-6', 8, 60 d.
Example 3
1, 6-dichloro-1, 6-dideoxy-~-D-fructofuranosyl-4, 6-dichloro-
`~?~ : 15 4,6-dideoxy-a-D-galactopyranoside (Compound 8)
A solution of 6,1',6'-trichloro-6,1',6'-trideoxysucrose (3g)
:.
in pyridine (70 ml) wa~ treated with sulphuryl chloride (35 ml) in dry
? ~ ~ ` : chloroform (100 ml) at -75 for 3 hours, The solution was stirred at
0 to -5 for 2 hours and then at room temperature for 24 hours, The
.20 reaction mixture was then diluted with dichloromethane (100 ml) and
,.~ washed successively with ice-cold sulphuric acid (10%, 250 ml), water,
: ?
.j aqueous sodium hydrogen carbonate, and water. The organic layer was
, . . .
dried over sodium sulphate and concentrated to give a syrup. The
- (13)
.
.
. ~ `
, . . .
`
~ 107tj~l~0 :
syrupy residue ~vas dissolved in methanol (100 ml) and dechlorosulphated
by means of excess barium carbonate and a catalytic amount of sodium
iodide. The inorganic residue was filtered off and the filtrate
concentrated to a syrup, T. l. c. ~chloroform - methanol, 4: 1) showed
the 4,6,1l,6'-tetrachloro-4,6,1l,6l-tetradeoxygalactosucrose as the
.
major product, A fast-moving rninor product, probably a pentachloro
derivative, was also observed. Purification on a column of silica gel,
using chloroform - acetone (5 :1) gave the tetrachloro derivative in
90% yield.
. ,
`~ :
Precisely equivalent results were obtained by repeating the
j .
;~ above procedure but starting from 1l,6'-dichloro-1',6l-dideoxysucrose
or l' -chloro-l' -deoxysucrose, instead of the 6,1', 6l -trichloro-6, 1l , 6l -
1
1~ ~ trideoxysucrose.
' i ' ' .
]D + 89 (C 1. O, methanol). Mass spectroscopy: mje 199
lS (2-Cl).
Tetra-acetate - white solid foam, [cr]D + 98. 5 (c 1, 0, CHC13),
10~ ME-Iz N, M, R, (CDC13, ~ values) - 4, 28 d (H-l), 5. 25 q (H-4),
.
4. 30 d (H-31 ), 4. 55 t (~I-41 ) Jl 2 3 5 Hz; J3 ,~ 3. 0 Hz; J4 5 1. 5 Hz;
J3, 4, 6, S Hz; J4, 51 6, S Hz, Mass spectrometry m/e 283 (2 Cl).
Tetra_mesylate - very pale yellow crystals from dichloro-
methane - ethanol m.p. 120-121; [']D + 65, 5 (c 1. 0, CHC13).
100 MHz N, M, R, (CDC13, ~ values) E~-l 4, 18 d (Jl 2 3 5 Hz);
(14)
.,
,. . .
.~
,'~ . .
.. ~, .
)76~.10
~;~ . j
H-~ 5. 06 q (J2 3 10 Hz); H-3 g. 77 q (J3 4 3. 5 Hz); H-4 5, 20 q
(J4 5 1- 5 EIz); H-3' 4. 39 d (J3, 4, 7. 0 Hz); H-4' 4. 65 t (J~, 5, 7. 0 Hz);
Mass spectrometry rn/e 355 (2 Cl).
,. 1 I ".
Example 4
4, 6, 1', 6'-tetrachlorosucrose (Compound 9)
~:'
~To a solution of 4, 6, 6' -trichloro-4, 6, 6' -trideoxy-2, 3, 3', 4' -
I ~ tetra-O-acetylgalactosucrose l'-O-monomesitylenesulphonate (lg) in
.
; D.M,F, (15 ml) was added excess of lithium chloride (2g) and a
eatalytic amount of iodine (50 mg) and the mixture was heated at
140-145 in an oil-bath for 18 hours. T. 1. c. (benzene - ethylacetate
3: 1) indicated the presence of a major product moving faster than the
~ - . - ........... ... . ... ..
- starting material. The reaction mixture was cooled, poured into ice-
- - .
~ ,~
cold water and then extracted with ethyl acetate, The organic extract
was washed thoroughly, first with 5% sodium thiosulphate solution and
15 ~ then with water, and dried, The ethyl acetate was evaporated off and
the residue was treated with methanol containing a catalytic amount of
sodium methoxide.
T. 1. c. (chloroform/acetone/methanol/water,
,:
57: 20: 20: 3) now showed the presence of a faster-moving minor product
and a slower-moving major product - both having very similar mobilities
::
and the latter corresponding to 4, 6,1', 6'-tetradeoxy-galactosucrose
(Compound 8) tmixed t. 1, c. ). The mixture was fractionated over a
eolumn of silica gel u~ing chloroform-methanol (10: 1) as eluent.
Although complete separation was not aehieved because of the close
(15)
,~ ,
;
.,:: ,. - . .
,
.
.: .. . .
' r . ~ ~ ,
1~7~ o
.
~. -
, , .
.
.. . . - ~
:
mobilities of the two components, the first few fractions contained
4, 6,1', 6'-tetrachloro-4, 6,1', 6'-tetradeoxy-sucrose which was obtained
as a white solid [~x]D + 45 (c 1, 0, MeOH). The structure was confirmed
by n. m. r. and mass spectrometry of the following derivatives:-
. . ~
~ 5 Tetra-acetate - syrup, [~]D + 30 5 (c 1, 0 CHC13) N, M, R.
. ~ . .
(C6D6 ~ ualues) - H-l, 4.39 d (Jl 2 4 35 Hz); H-2, 5~14 q~J2 3 10 Hz.~;
H-3, 4.27 t (J8 4 10 Hz); H-4, 6.1 t (J4 5 10 Hz); H-3', 4.20 d
(J3~ 4~ 9- 6 Hz); H-4'~ 4- 62 t (J4, 5, 6, 0 Hz),
Tetra-mesylate - white crystalline compound m.p. 187
~ ~ ~ ' r,, }
~dichloromethane - methanol) [~]D + 29, 9 (c 1, 0, acetone).
Example 5
, ~ ~ Sweetening tablets for ~L~4!
Each tablet contains:
, ~ Compound 3 8 mg
.or Compound 5 2 mg
,.. i .
together with a dispersable tablet base (ca. 60mg) containing sucrose,
gum arabic and magnesium stearate, and is equivalent in sweetness to
,` about 4, 5 g sucrose.
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', Example 6
ulked sweetener
A bulked sweetener having the same sweetness as an equivalent volume
~ of sucrose (granulated sugar) i~ prepared by mixing the following
';, S mgredients and spray-dryin~ to~ a bulk density of 0. 2 g/cc: ' '
;~
maltodextrin solutlon containing dry weight 222. 2 g
~ ~ . Compound 3 ' 1, 7 g
" l ~ (or Compound S 0, 5 g),
The resulting composition has a sweetening power equivalent to
~ approximately 2 kilograms of sugar.
Example 7
Reduced calorle cola drink containing sugar
Ingredients to prepare 100 ml bottling syrup:~
Compound 3 80 mg
l5 ~ ~ (or Compound 5 , 20 mg )
Sugar 60 g
Benzolc acid 35 mg
Phosphoric acid (conc. ) 1 ml
Cola flavour 1,1 ml
Colour ad-lib.
,, Make up t ,o, l OO ml with mine ral wate r,
This syrup may then~ be added in 25 ml doses to carbonated 225 ml
, aliquots of chilled mineral water.
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Example 8
Carbonated low calorie lemonade (sugar-free)
.. .
Ingredients to prepare 100 ml syrup:
" . ~ .
- i Compound 3 100 mg
i 5 (or Compound 5 19 mg )
; ~, Benzoic acid 35 mg
Citric acid (dry base) 1. 67 g
!
1 ~.
~ Lemon essence ` 0. 8 g :
"-` '~ ''I , , .
Make up to 100 ml in mineral water.
10~ ~ This syrup can be added in 25 ml doses to 225 ml aliquots of
carbonated chilled mineral water.
Exarnple 9
Toothpaste
% by weight
Dibasic calcium phosphate 50%
Glycerol 20%
~ ., ., . ~ ,
Sodium lauryl sulphate 2, 5%
. .", ~
Spearmint oil 2. 5%
Gum tragacanth 1. 0%
Compound 3 0, 03%
,~ Water 2 3 . 97%
' '3~ ~: ' ''
The ingredients are mixed to produce a spearmint flavoured toothpaste
of acceptable sweetness but free from sugar or saccharin,
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,: Example 10
~, Chewil~C~um
,;;1 , .
part by weight
:,
Polyvinyl acetate 20
6 Butyl phthalylbutylglycolate 3
Polyisobutylene 3
, ,
Microcrystalline wax 2
: ~ Calcium carbonate 2
Flavouring/aroma ; 1
:10 ~ : ~ Compound 3 ' ~ 0. 07
Glucose 10
:The above chewing gum base can be cut into conventional tablets or
strips,
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