CA1037491A - Acyl-phenoxy-propanesulfoacids and salts, and artificial sweetening compositions containing the same - Google Patents
Acyl-phenoxy-propanesulfoacids and salts, and artificial sweetening compositions containing the sameInfo
- Publication number
- CA1037491A CA1037491A CA220,317A CA220317A CA1037491A CA 1037491 A CA1037491 A CA 1037491A CA 220317 A CA220317 A CA 220317A CA 1037491 A CA1037491 A CA 1037491A
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- Prior art keywords
- general formula
- compound
- hydroxy
- salt
- phenyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Seasonings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New compounds of the general formula (I), or their salts (I) are prepared as follows:
a) a compound of the general formula (II) (II) is reduced; or b) a compound of the general formula (III) (III) is reacted, optionally after protecting the phenolic hydroxy group attached to position 3 of the ring, with a compound of the general formula (IV), (IV) or c) group R1 of a compound of the general formula (V) (V) is removed in an acidic medium, and, if desired, a compound of the general formula (I) is converted into its salt, or a salt of a compound of the general formula (I) is converted into the free acid or an-other salt thereof.
The compounds of the general formula (I) and their salts are valuable artificial sweetening agents.
In the above formulae "alkyl" stands for a C1-4 alkyl group, R stands for hydrogen or a protecting group capable to split off upon hydrogenolysis, preferably benzyl or benzyloxy-carbonyl group, M+ stands for a proton or another cation, X stands for a group of the general formula O-M+, Y stands for halogen, or X and Y may represent together an oxygen atom, and R1 stands for a protecting group capable of splitting off in acidic media, such as 2-tetrahydropyranyl or 1-ethoxyethyl group.
New compounds of the general formula (I), or their salts (I) are prepared as follows:
a) a compound of the general formula (II) (II) is reduced; or b) a compound of the general formula (III) (III) is reacted, optionally after protecting the phenolic hydroxy group attached to position 3 of the ring, with a compound of the general formula (IV), (IV) or c) group R1 of a compound of the general formula (V) (V) is removed in an acidic medium, and, if desired, a compound of the general formula (I) is converted into its salt, or a salt of a compound of the general formula (I) is converted into the free acid or an-other salt thereof.
The compounds of the general formula (I) and their salts are valuable artificial sweetening agents.
In the above formulae "alkyl" stands for a C1-4 alkyl group, R stands for hydrogen or a protecting group capable to split off upon hydrogenolysis, preferably benzyl or benzyloxy-carbonyl group, M+ stands for a proton or another cation, X stands for a group of the general formula O-M+, Y stands for halogen, or X and Y may represent together an oxygen atom, and R1 stands for a protecting group capable of splitting off in acidic media, such as 2-tetrahydropyranyl or 1-ethoxyethyl group.
Description
/~ ~
~ 74g~ ~
This invention relates to new acyl-phenoxy-propane-sulfoacids and salts, to artificial sweetening compositions containing the same, as well as to a process for the preparation thereof.
As known, artificial sweeteners without caloricity are essential both for diabetics and healthy persons with excess body weight. As artificial sweeteners, cyclamate and saccharin are commonly used in recent practice. ~1-though the use of cyclamate is prohibited in some countries, and the saccharin substances steadily lose their importance owing to their unpleasant after- ;~
taste, no other artificial sweetening agent equivalent to these compounds has been marketed so far. Several saccharin-compositions are known in which the favourable sweetening ability of saccharin is utilized, and tho unpleasant after-taste is attempted to be suppressed with sugar or other additivcs rich in calory. Thus~ for instance~ United States pattdnt spoci~ication No.
3,743,518 describes a mixture in which 1 part by weight of calcium saccharide or sodium saccharide is mixed with about 5 parts by weight of fructose and 10 to 15 parts by weight of calcium or sodium gluconate or glucono-~ lactone, respectively. United States patent specification No. 3,087~821 describes hesperetin-dihydrochalcon-glucoside as a compound with intense sweet taste and applicable as artificial sweetener, and United States patent specification No. 3,429,873 describes the preparation of these compounds from the hesperetine- ~
like natural flavononglucosides occurring in citruses. The extremely specific ;~` `
nature of sweet taste is re Mected by the fact that hesperetine-dihydro-chalcon-rhutinoside is a tasteless substance, whereas the glucoside formed by splitting an L-rhamnose molecule from this compound has already a sweetcning value equivalent to that of saccharin. The preparation of dihydrochalcon-a~oxycarboxylic acid derivatives and their salts is described in Hungarian patent specification No. 163,394.
This invention relates to novel acyl-phenox~-propane-sulfoacids of ;~
the general formula (I), ~e 749~ ;
C~ C~ '~
C~2 ~ / 2 2 ~ 0H
OH Oalkyl wherein "alkyl~ stands for a Cl ~ alkyl group, and to the salts thereof.
These compounds are very well soluble, thermally skable, resistant to the action of acids, and non-toxic. They have great sweatening values, and have no unpleasant by-flavour. Thus these compounds, optionally in combin-ation with additives, indifferent salts or other sweetening agents, can be applied ko great advantage for sweetening foodstu~fs, pharrnaccuticals, ctc.
As additives, e.g. diluents~ solvents, carriers~ substances promoting thc im-pression of ~weet taste, etc. can be used, either alone or in combination with each other. The invention also relates to a method for flavouring (sweetening) foodstuffs and pharmaceuticals.
s The most preferred group of the new compoundvs having the general formula (I) includes the following substances: 1-(2-hydroxy-4-/3-sulfo-propyl-1 oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propane-1-one and salts~ 1-(2- -~
hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3 hydroxy-4-ethoxyphenyl)-propane-l-one and salts, l-(2-hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy~phenyl)-propane-l-one and salts, 1-(2-hydroxy-5-/3-sulfo-propyl~
oxy/ -phenyl~-3-(3-hydroxy-4-ethoxyphenyl)-propane-1-one and salts.
As mentioned above, the invention also relates to a process for the preparation of compounds having the general formula (I) or the salts thereof.
These compounds can be prepared in accordance with the invention by any of the following process variants:
a) a compound of the general formula (II), '
~ 74g~ ~
This invention relates to new acyl-phenoxy-propane-sulfoacids and salts, to artificial sweetening compositions containing the same, as well as to a process for the preparation thereof.
As known, artificial sweeteners without caloricity are essential both for diabetics and healthy persons with excess body weight. As artificial sweeteners, cyclamate and saccharin are commonly used in recent practice. ~1-though the use of cyclamate is prohibited in some countries, and the saccharin substances steadily lose their importance owing to their unpleasant after- ;~
taste, no other artificial sweetening agent equivalent to these compounds has been marketed so far. Several saccharin-compositions are known in which the favourable sweetening ability of saccharin is utilized, and tho unpleasant after-taste is attempted to be suppressed with sugar or other additivcs rich in calory. Thus~ for instance~ United States pattdnt spoci~ication No.
3,743,518 describes a mixture in which 1 part by weight of calcium saccharide or sodium saccharide is mixed with about 5 parts by weight of fructose and 10 to 15 parts by weight of calcium or sodium gluconate or glucono-~ lactone, respectively. United States patent specification No. 3,087~821 describes hesperetin-dihydrochalcon-glucoside as a compound with intense sweet taste and applicable as artificial sweetener, and United States patent specification No. 3,429,873 describes the preparation of these compounds from the hesperetine- ~
like natural flavononglucosides occurring in citruses. The extremely specific ;~` `
nature of sweet taste is re Mected by the fact that hesperetine-dihydro-chalcon-rhutinoside is a tasteless substance, whereas the glucoside formed by splitting an L-rhamnose molecule from this compound has already a sweetcning value equivalent to that of saccharin. The preparation of dihydrochalcon-a~oxycarboxylic acid derivatives and their salts is described in Hungarian patent specification No. 163,394.
This invention relates to novel acyl-phenox~-propane-sulfoacids of ;~
the general formula (I), ~e 749~ ;
C~ C~ '~
C~2 ~ / 2 2 ~ 0H
OH Oalkyl wherein "alkyl~ stands for a Cl ~ alkyl group, and to the salts thereof.
These compounds are very well soluble, thermally skable, resistant to the action of acids, and non-toxic. They have great sweatening values, and have no unpleasant by-flavour. Thus these compounds, optionally in combin-ation with additives, indifferent salts or other sweetening agents, can be applied ko great advantage for sweetening foodstu~fs, pharrnaccuticals, ctc.
As additives, e.g. diluents~ solvents, carriers~ substances promoting thc im-pression of ~weet taste, etc. can be used, either alone or in combination with each other. The invention also relates to a method for flavouring (sweetening) foodstuffs and pharmaceuticals.
s The most preferred group of the new compoundvs having the general formula (I) includes the following substances: 1-(2-hydroxy-4-/3-sulfo-propyl-1 oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propane-1-one and salts~ 1-(2- -~
hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3 hydroxy-4-ethoxyphenyl)-propane-l-one and salts, l-(2-hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy~phenyl)-propane-l-one and salts, 1-(2-hydroxy-5-/3-sulfo-propyl~
oxy/ -phenyl~-3-(3-hydroxy-4-ethoxyphenyl)-propane-1-one and salts.
As mentioned above, the invention also relates to a process for the preparation of compounds having the general formula (I) or the salts thereof.
These compounds can be prepared in accordance with the invention by any of the following process variants:
a) a compound of the general formula (II), '
-2-: ~37~9~
fl .~ , C - CH = CH OR
H2C -O ~ ~ (II~
CH2 OH Oalkyl wherein "alkyl" stands for a Cl 4 alkyl group, R stands for hydrogen or a protecting group capable to split off upon hydrogenolysis~ such as benzyl or benzyloxycarbonyl group, and M stands for a proton or another cation, is . reduced; or b) a compound of the general formula (III)~ `:
.' l ~ ~ `:
HO ~ OH ~ Oall~yl (III) . .
wherein ~'alkyl" has the same meanings as defined above, is reacted, optionally i after protecting the phenolic hydroxy group attached to position 3 of the ring, with a compound of the general formula (IV)~ :
.. , ~ .
CH2 2 ~ ; ;
wherein X stands for a group of ~he general formula O M and Y stands for ": .': ': . , .::
halogen~ or X and Y represent together an oxygen atom; or c) group R of a compound of the general formula (V)~
H2C -O ~ C - C~ - C~ ~ O*
CH2 OH Oalkyl ~03 M
wherein R stands for a protecting group capable of splitting off in acidic media~ such as 2-tetrahydropyranyl or l-ethoxyethyl group~ and M and ~alkyl~
fl .~ , C - CH = CH OR
H2C -O ~ ~ (II~
CH2 OH Oalkyl wherein "alkyl" stands for a Cl 4 alkyl group, R stands for hydrogen or a protecting group capable to split off upon hydrogenolysis~ such as benzyl or benzyloxycarbonyl group, and M stands for a proton or another cation, is . reduced; or b) a compound of the general formula (III)~ `:
.' l ~ ~ `:
HO ~ OH ~ Oall~yl (III) . .
wherein ~'alkyl" has the same meanings as defined above, is reacted, optionally i after protecting the phenolic hydroxy group attached to position 3 of the ring, with a compound of the general formula (IV)~ :
.. , ~ .
CH2 2 ~ ; ;
wherein X stands for a group of ~he general formula O M and Y stands for ": .': ': . , .::
halogen~ or X and Y represent together an oxygen atom; or c) group R of a compound of the general formula (V)~
H2C -O ~ C - C~ - C~ ~ O*
CH2 OH Oalkyl ~03 M
wherein R stands for a protecting group capable of splitting off in acidic media~ such as 2-tetrahydropyranyl or l-ethoxyethyl group~ and M and ~alkyl~
-3-`:, ~0;~7~L ;`` ~
each have the same meanings as defined above, is removed in an acidic medium, and, if desired, a compound of the general formula (I) is conver~ed to its salt, or a salt of a compound of the general formula ~I) is converted into the free acid or another salt thereof.
When M stands for a cation, it may represent preferably an alkali metal (such as sodium or potassium)~ an alkaline earth metal (such as calcium or magnesium) or ammonium ion. ;
~hen Y stands for halogen, it may represent preferably chlorine, ;~
bromine or iodine.
In Method a) of the invention~ a compound of the general Pormula (II) is reduced preferably by(catalytic hydrogenat:ion. As catalyst~ e.g.
palladium, preferably supported e g on carbon, p:Latinum, or Raney-nickel can be used. The hydrogenation is perfo~med in a so~vent7 preferably in water~
at room temperature or with heating, under atmospheric or superatmospheric pressure . '., In Method b) of the invention, a compound of the general formula (III) is reacted with a compound of the general formula (IV) either at room temperature in the presence of a solvent, preferably water or dimethylform-amide, or by fusing the reactants in the absence o~ solvent. In both in-stances an acid binding agent, pre~erably an alkali metal hydroxide, carbonate ~ -or hydrocarbonate, is added to the reaction mixture. As the reactant of the general formula ~IV), preferabl~ propanesultone or a 3~halo-1-propanesulfonic acid, or a salt thereof can be ~lsed.
In Method c) of the invention, the protecting group is split off preferably in a hydrochloric acid medium.
The starting substances of the above process variants can be pre-pared as follows:
The compounds of the general formula (II) can be prepared by con-densing a salt of a sulfoacid of the formula .~ r -'1- :
~ 749~
CO -CH
H03S ~CH2 -CH2 -CH2 - O ~ (VI) OH
with a compound of the general formula (YII~, H OR
O = C ~ (VII) ~ Oalkyl wherein R and "alkyl~' each have the same meanings as defined above. The con-densation is carried out at room temperature, in the presence of an aqueous solution of an alka:Li metal hydroxide? preferably sodium or potassium hy~
droxide. According to another method, the compounds of the gencra:L formu:La (II) can be prepared by reacting a compound of thc genoraL formula (VIII)7 ,., :
~ ~ CH = CH ~ OR
HO ~ OH ~ Oalkyl (VIII) wherein R and "alkyl" each have the same meanings as defined above, with a ~-compound of the general formula (IV). This reaction is carried out at room temperature in a solvent, preferably water, in the presence of an acid binding agent, such as an alkali metal hydroxide, carbonate or hydrocarbonate. ~ -~
The compounds o-f the general formula ~III), used as starting sub-stances according to Method b), can be prepared by reducing the corresponding compounds of the general formula (YIII~. The reduction is performed pref-erably by catalytic hydrogenation in a solvent, particularly water, at room temperature or with heating.
The salts of the acyl-phenoxy-propanesulfoacids of the general formula ~I) can be prepared preferably by neutralizing the free acid with an oxide or hydroxide of the appropriate metal~ or with a salt of the metal formed with a weak acid, preferably with its carbonate or hydrocarbonate. The salts 7~L
can also be converted into salts formed with other metal ions. In this in-stance preferably a poorly water-soluble salt of the acid of the general formula (I), such as the calcium salt, is prepared first, and ~hen this salt `~
is treated with the sulfate of the appropriate metal. The calcium sulfate by-product is removed by filtration, and the obtained salt is separated from the aqueous solution preferably by evaporation or direct crystallization.
The invention is elucidated in detail by the aid of the following non-limiting Examples.
. ~ ,.
10 g. of sodium hydrocarbonate are added to the suspension of 15.2 g.
of 2,4-dihydroxyacetophenone in 30 ml. of water~ and the mixturo is heated cautiously until a homogeneous solution is obtained Tho react:Lon mi~turc is cooled to O~C; on cooling thc salt of the aoetophenone rcactant separates.
Propanesultone is added to the suspension in an amount corresponding to 6.8 g.
; of pure substance, during this operation the mixture is vigorously stirred.
The mixture is stirred at about 0C for 2 hours, and then heated on a steam bath for 15 minutes. The optionally acidic solution is neutralized, and thereafter acidified to pH = 2 with concentrated hydrochloric acid. The mix-ture is cobled to 0C, the separated product is filtered Offg washed with a ., ~ .
few amount of ice water, dried, then suspended in acetone, filtered again, and dried. 10.5 g. (72 %) of 2-hydroxy-4-(3-sulfo-propyl-1-oxy)-acetophenone sodium salt are obtained, m.p.:~ 300 C.
Example 2 A mixture of 5.0 g. of 2-hydroxy-4-(3-sulfo-prop~ oxy)-aceto-phenone sodium salt, 2.6 g. of isovanillin and 17 ml. of 8 N sodium hydroxide solution is stirred at room temporature f~r 48 hours. The yellow suspension ~ ;
is acidified with 10 % hydrochloric acid, the separated substance is filtered off~ suspended in 50 ml. of acetone, filtered off again, and dried. 6.o g.
(82 ~) of 2~3-dihydroxy-4-methoxy-4~-(3-sulfo-propyl-1-oxy)-chalcon sodium ~0;~749~
salt are obtained; m.p.: 273-276 C. If desired, this product can be purified further by recrystalli~ation from water.
Exa ple 3 A mixture of 14.4 g. of 2-hydroxy-4-(3-sulfo~propyl-1-oxy)-aceto-phenone sodium salt, 8.o g. of 3-hydroxy-4-ethoxy-benzaldehyde and 60 ml. of a 8 N sodium hydroxide solution is stirred at room temperature for 96 hours.
The yellow suspension is acidified with 10 % hydrochloric acid~ the separated crude product is filtered off, and recrystallized twice from water. 6.o g.
(28 %) of 2~,3-dihydroxy-4-ethoxy-4~-~3-sulfo-propyl-1-oxy)-chalcon sodium salk are obtained. The product shrinks at 250C without melting.
~ ' .: :' A solution of 5.0 g. of 2~3-dihydroxy-4-ethoxy-4~-(3-9ulfo-propy:l-l-oxy)-chalcon sodium salt in 50 ml. of water is hydrogonated at 60C, in the presence of 1 g. of palladium/carbon catalyst~ until the uptake of the cal-culated amount of hydrogen. The mixture is filtered~ the filtrate is evaporat-ed to dryness, and the residue is recrystallized twice from minimum amount of water. 2.0 g. (40 %) of 1-(2-hydroxy-4-/3-sulfonyl-propyl-1-oxy/-phenyl)-3-(3_hydroxy-4_ethoxyphenyl)-propanone-1 are obtained, m.p.: 239-241 C (de-composition).
xample 5 A solution of 20 g. of 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)- `
3_(3-hydroxy-4-methoxyphenyl) prop-2-ene-1-one sodium salt in 100 ml. of water `~
is hydrogenated at 60 C in the presence of 4 g. of palladium/carbon until the ;
uptake of the calculated amount of hydrogen. The mixture is heated to 95 C~ the catalyst is filtered off, and the filtrate is cooled. The sep~rated substance is filtered off,~washed with a few amount of ice water, and dried. 13 to 14 g.
(65 to 70 %) of 1-~2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4- `'!
methoxyphenyl)_propanone-l are obtained; m.p.: 257-258 a (decomposition).
'`' ' ~,' ' . ' i, .,,, ':;,, .. ~ . ,., .. ,. . , .. , . ., . . ~
~ID3749~ :
Example 6 10 g. of 1-~2-hydroxy-4-/3-sulfo~propyl-1-oxy/-phenyl)-3-(3-benzyl-oxy-4-methoxyphenyl)-prop-2-ene-1-one are ad~ed to pre-hydrogenated palladium/
carbon catalyst in 50 ml. of water, and the obtained suspension is stirred at 60 C until the uptake of 2 molar equivalents of hydrogen. The solution is filtered when hot, and the filtrate is cooled. 7.0 g. of 1-(2-hydroxy-4-/3-sulfo_propyl-l-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-prop~none-1 are obtained.
Example 7 10 g. of 1-(2-hydroxy-4-/3-sulfo-1-propyl-1-oxy/~phenyl)-3-(3-/2-tetrahydropyranyloxy/-4-methoxyphenyl)-prop-2-ene-/-one are added to palladium/
carbon catalyst pre-hydrogenated in 50 ml. of water, and thc o~tained suspon~
sion is stirred at 60 C until the uptake of one molar e~uivalont of hydrogen.
The catalyst is removed by filtration~ 1 ml. of concentrated hydrochloric acid is added to the filtrate, and the mixture is heated at 90 C for 20 minutes. On cooling~ 6.5 g. oX 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propanone_l separate from the solution.
~ , ' .
7.2 g. of 1-(2,4-dihydroxyphenyl)-3-~3-/2-tetrahydropyranyloxy/-4-20 methoxyphenyl)-propanone-l are dissolvèd in 22 ml. of a 1 N sodium hydroxide ~ ;
solution, and 2.68 g. of propanesultone are added to the solution in portions within one hour. The solution is heated on a steam bath for 15 minutes, thereafter 2 ml. of concentrated hydrochloric acid are added, and heating is continu0d for additional 20 minutes. The sol~ltion is filtered when hot, and the filtrate i~ cooled. 4.0 g~ of 1-(2-hydroxy-4-t3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propanone-1 are obtained.
Example 9 The sodium salt of 1-~2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3_hydroxy-4-methoxyphenyl) propanone-l can be converted into other salts r : , .: '' '' , ~ ; ' :
- ~3~4~9~ :
via the poorly soluble calcium salt. An excess of a calcium chloride solu-tion is added to the warm, concentrated aqueous solution of the sodium salt~
the separated calcium salt is filtered off, washed sodium-free, then suspended in hot water~ and an equivalent amount of the sulfate of the appropriate metal is added. The suspension :is stirred with heating for about one-half hours~ the separated calcium sulfate is removed by filtration~ and the filtrate is evaporated, or the obtained salt is allowed to crystallize, respectively. ~
:',.: . ~, ~' ".
,'"
~,j,,, . .
_9_ ~
each have the same meanings as defined above, is removed in an acidic medium, and, if desired, a compound of the general formula (I) is conver~ed to its salt, or a salt of a compound of the general formula ~I) is converted into the free acid or another salt thereof.
When M stands for a cation, it may represent preferably an alkali metal (such as sodium or potassium)~ an alkaline earth metal (such as calcium or magnesium) or ammonium ion. ;
~hen Y stands for halogen, it may represent preferably chlorine, ;~
bromine or iodine.
In Method a) of the invention~ a compound of the general Pormula (II) is reduced preferably by(catalytic hydrogenat:ion. As catalyst~ e.g.
palladium, preferably supported e g on carbon, p:Latinum, or Raney-nickel can be used. The hydrogenation is perfo~med in a so~vent7 preferably in water~
at room temperature or with heating, under atmospheric or superatmospheric pressure . '., In Method b) of the invention, a compound of the general formula (III) is reacted with a compound of the general formula (IV) either at room temperature in the presence of a solvent, preferably water or dimethylform-amide, or by fusing the reactants in the absence o~ solvent. In both in-stances an acid binding agent, pre~erably an alkali metal hydroxide, carbonate ~ -or hydrocarbonate, is added to the reaction mixture. As the reactant of the general formula ~IV), preferabl~ propanesultone or a 3~halo-1-propanesulfonic acid, or a salt thereof can be ~lsed.
In Method c) of the invention, the protecting group is split off preferably in a hydrochloric acid medium.
The starting substances of the above process variants can be pre-pared as follows:
The compounds of the general formula (II) can be prepared by con-densing a salt of a sulfoacid of the formula .~ r -'1- :
~ 749~
CO -CH
H03S ~CH2 -CH2 -CH2 - O ~ (VI) OH
with a compound of the general formula (YII~, H OR
O = C ~ (VII) ~ Oalkyl wherein R and "alkyl~' each have the same meanings as defined above. The con-densation is carried out at room temperature, in the presence of an aqueous solution of an alka:Li metal hydroxide? preferably sodium or potassium hy~
droxide. According to another method, the compounds of the gencra:L formu:La (II) can be prepared by reacting a compound of thc genoraL formula (VIII)7 ,., :
~ ~ CH = CH ~ OR
HO ~ OH ~ Oalkyl (VIII) wherein R and "alkyl" each have the same meanings as defined above, with a ~-compound of the general formula (IV). This reaction is carried out at room temperature in a solvent, preferably water, in the presence of an acid binding agent, such as an alkali metal hydroxide, carbonate or hydrocarbonate. ~ -~
The compounds o-f the general formula ~III), used as starting sub-stances according to Method b), can be prepared by reducing the corresponding compounds of the general formula (YIII~. The reduction is performed pref-erably by catalytic hydrogenation in a solvent, particularly water, at room temperature or with heating.
The salts of the acyl-phenoxy-propanesulfoacids of the general formula ~I) can be prepared preferably by neutralizing the free acid with an oxide or hydroxide of the appropriate metal~ or with a salt of the metal formed with a weak acid, preferably with its carbonate or hydrocarbonate. The salts 7~L
can also be converted into salts formed with other metal ions. In this in-stance preferably a poorly water-soluble salt of the acid of the general formula (I), such as the calcium salt, is prepared first, and ~hen this salt `~
is treated with the sulfate of the appropriate metal. The calcium sulfate by-product is removed by filtration, and the obtained salt is separated from the aqueous solution preferably by evaporation or direct crystallization.
The invention is elucidated in detail by the aid of the following non-limiting Examples.
. ~ ,.
10 g. of sodium hydrocarbonate are added to the suspension of 15.2 g.
of 2,4-dihydroxyacetophenone in 30 ml. of water~ and the mixturo is heated cautiously until a homogeneous solution is obtained Tho react:Lon mi~turc is cooled to O~C; on cooling thc salt of the aoetophenone rcactant separates.
Propanesultone is added to the suspension in an amount corresponding to 6.8 g.
; of pure substance, during this operation the mixture is vigorously stirred.
The mixture is stirred at about 0C for 2 hours, and then heated on a steam bath for 15 minutes. The optionally acidic solution is neutralized, and thereafter acidified to pH = 2 with concentrated hydrochloric acid. The mix-ture is cobled to 0C, the separated product is filtered Offg washed with a ., ~ .
few amount of ice water, dried, then suspended in acetone, filtered again, and dried. 10.5 g. (72 %) of 2-hydroxy-4-(3-sulfo-propyl-1-oxy)-acetophenone sodium salt are obtained, m.p.:~ 300 C.
Example 2 A mixture of 5.0 g. of 2-hydroxy-4-(3-sulfo-prop~ oxy)-aceto-phenone sodium salt, 2.6 g. of isovanillin and 17 ml. of 8 N sodium hydroxide solution is stirred at room temporature f~r 48 hours. The yellow suspension ~ ;
is acidified with 10 % hydrochloric acid, the separated substance is filtered off~ suspended in 50 ml. of acetone, filtered off again, and dried. 6.o g.
(82 ~) of 2~3-dihydroxy-4-methoxy-4~-(3-sulfo-propyl-1-oxy)-chalcon sodium ~0;~749~
salt are obtained; m.p.: 273-276 C. If desired, this product can be purified further by recrystalli~ation from water.
Exa ple 3 A mixture of 14.4 g. of 2-hydroxy-4-(3-sulfo~propyl-1-oxy)-aceto-phenone sodium salt, 8.o g. of 3-hydroxy-4-ethoxy-benzaldehyde and 60 ml. of a 8 N sodium hydroxide solution is stirred at room temperature for 96 hours.
The yellow suspension is acidified with 10 % hydrochloric acid~ the separated crude product is filtered off, and recrystallized twice from water. 6.o g.
(28 %) of 2~,3-dihydroxy-4-ethoxy-4~-~3-sulfo-propyl-1-oxy)-chalcon sodium salk are obtained. The product shrinks at 250C without melting.
~ ' .: :' A solution of 5.0 g. of 2~3-dihydroxy-4-ethoxy-4~-(3-9ulfo-propy:l-l-oxy)-chalcon sodium salt in 50 ml. of water is hydrogonated at 60C, in the presence of 1 g. of palladium/carbon catalyst~ until the uptake of the cal-culated amount of hydrogen. The mixture is filtered~ the filtrate is evaporat-ed to dryness, and the residue is recrystallized twice from minimum amount of water. 2.0 g. (40 %) of 1-(2-hydroxy-4-/3-sulfonyl-propyl-1-oxy/-phenyl)-3-(3_hydroxy-4_ethoxyphenyl)-propanone-1 are obtained, m.p.: 239-241 C (de-composition).
xample 5 A solution of 20 g. of 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)- `
3_(3-hydroxy-4-methoxyphenyl) prop-2-ene-1-one sodium salt in 100 ml. of water `~
is hydrogenated at 60 C in the presence of 4 g. of palladium/carbon until the ;
uptake of the calculated amount of hydrogen. The mixture is heated to 95 C~ the catalyst is filtered off, and the filtrate is cooled. The sep~rated substance is filtered off,~washed with a few amount of ice water, and dried. 13 to 14 g.
(65 to 70 %) of 1-~2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4- `'!
methoxyphenyl)_propanone-l are obtained; m.p.: 257-258 a (decomposition).
'`' ' ~,' ' . ' i, .,,, ':;,, .. ~ . ,., .. ,. . , .. , . ., . . ~
~ID3749~ :
Example 6 10 g. of 1-~2-hydroxy-4-/3-sulfo~propyl-1-oxy/-phenyl)-3-(3-benzyl-oxy-4-methoxyphenyl)-prop-2-ene-1-one are ad~ed to pre-hydrogenated palladium/
carbon catalyst in 50 ml. of water, and the obtained suspension is stirred at 60 C until the uptake of 2 molar equivalents of hydrogen. The solution is filtered when hot, and the filtrate is cooled. 7.0 g. of 1-(2-hydroxy-4-/3-sulfo_propyl-l-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-prop~none-1 are obtained.
Example 7 10 g. of 1-(2-hydroxy-4-/3-sulfo-1-propyl-1-oxy/~phenyl)-3-(3-/2-tetrahydropyranyloxy/-4-methoxyphenyl)-prop-2-ene-/-one are added to palladium/
carbon catalyst pre-hydrogenated in 50 ml. of water, and thc o~tained suspon~
sion is stirred at 60 C until the uptake of one molar e~uivalont of hydrogen.
The catalyst is removed by filtration~ 1 ml. of concentrated hydrochloric acid is added to the filtrate, and the mixture is heated at 90 C for 20 minutes. On cooling~ 6.5 g. oX 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propanone_l separate from the solution.
~ , ' .
7.2 g. of 1-(2,4-dihydroxyphenyl)-3-~3-/2-tetrahydropyranyloxy/-4-20 methoxyphenyl)-propanone-l are dissolvèd in 22 ml. of a 1 N sodium hydroxide ~ ;
solution, and 2.68 g. of propanesultone are added to the solution in portions within one hour. The solution is heated on a steam bath for 15 minutes, thereafter 2 ml. of concentrated hydrochloric acid are added, and heating is continu0d for additional 20 minutes. The sol~ltion is filtered when hot, and the filtrate i~ cooled. 4.0 g~ of 1-(2-hydroxy-4-t3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxyphenyl)-propanone-1 are obtained.
Example 9 The sodium salt of 1-~2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3_hydroxy-4-methoxyphenyl) propanone-l can be converted into other salts r : , .: '' '' , ~ ; ' :
- ~3~4~9~ :
via the poorly soluble calcium salt. An excess of a calcium chloride solu-tion is added to the warm, concentrated aqueous solution of the sodium salt~
the separated calcium salt is filtered off, washed sodium-free, then suspended in hot water~ and an equivalent amount of the sulfate of the appropriate metal is added. The suspension :is stirred with heating for about one-half hours~ the separated calcium sulfate is removed by filtration~ and the filtrate is evaporated, or the obtained salt is allowed to crystallize, respectively. ~
:',.: . ~, ~' ".
,'"
~,j,,, . .
_9_ ~
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the general formula (I), (I) wherein "alkyl" stands for a C1-4 alkyl group, or a salt thereof.
2. 1-(2-Hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy phenyl)-propanone-1 or its salts.
3. 1-(2-Hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-ethoxyphenyl)-propanone-1 or its salts.
4. 1-(2-Hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy phenyl)-propanone-1 or its salts.
5. 1-(2-Hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-ethoxy-phenyl)-propanone-1 or its salts.
6. A process for the preparation of a new acylphenoxy-propanesulfoacid of the general formula (I), (I) wherein "alkyl" stands for a C1-4 alkyl group, or a salt thereof, in which a) a compound of the general formula (II), (II) wherein "alkyl" stands for a C1-4 alkyl group, R stands for hydrogen or a protecting group capable to split off upon hydrogenolysis, preferably a benzyl or benzyloxycarbonyl group, and M+ stands for a proton or another cation, is reduced; or b) a compound of the general formula (III) (III) wherein "alkyl" has the same meanings as defined above, is reacted optionally after protecting the phenolic hydroxy group attached to position 3 of the ring, with a compound of the general formula (IV), (IV) wherein X stands for a group of the general formula O?M+ and Y stands for halogen, or X and Y represent together an oxygen atom; or c) group R1 of a compound of the general formula (V), (V) wherein R1 stands for a protecting group capable of splitting off in acidic media, such as 2-tetrahydropyranyl or 1-ethoxyethyl group, and M+ and "alkyl"
each have the same meanings as defined above, is removed in an acidic medium, and, if desired, a compound of the general formula (I) is converted into its salt, or a salt of a compound of the general formula (I) is converted into the free acid or another salt thereof.
each have the same meanings as defined above, is removed in an acidic medium, and, if desired, a compound of the general formula (I) is converted into its salt, or a salt of a compound of the general formula (I) is converted into the free acid or another salt thereof.
7. A proeess as claimed in variant b) of claim 6, in which the reactant of the general formula (IV) is propanesulton, a 3-halo-1-propanesulfoacid, or a salt thereof.
8. A process as claimed in variant a) of claim 6, in which a compound of the general formula (II), prepared by reaeting a salt of a compound of the formula (VI) (VI) with a compound of the general formula (VII) (VII) wherein R and "alkyl" each have the same meanings as defined in claim 6, is used as starting substance.
9. A process as claimed in variant a) of claim 6, in which a compound of the general formula (II), prepared by reacting a compound of the general formula (VIII), (VIII) wherein R and "alkyl" each have the same meanings as defined in claim 6, with a compound of the general formula (IV), wherein X and Y each have the same meanings as defined in claim 6, is used as starting substance.
10. A process as claimed in variant b) of claim 6, in which a compound of the general formula (III), prepared by reducing a compound of the general formula (VIII), wherein R and "alkyl" each have the same meanings as defined in claim 6, is used as starting substance.
11. A process as claimed in variant a) of claim 6, in which the re-duction is carried out by catalytic hydrogenation in the presence of platinum, palladium/carbon, Raney-nickel or palladium.
12. A process as claimed in claim 11, in which the catalytic hydro-genation is performed in a solvent, preferably in water, at or above room temperature.
13. A process as claimed in claim 11 or 12, in which the catalytic hydrogenation is performed under atmospheric or superatmospheric pressure.
14. A process as claimed in variant b) of claim 6.
in which the reaction is carried out either at room temperature in the presence of a solvent, preferably water or dimethyl-formamide, or by fusing the reactants in the absence of solvent.
in which the reaction is carried out either at room temperature in the presence of a solvent, preferably water or dimethyl-formamide, or by fusing the reactants in the absence of solvent.
15. A process as claimed in variant b) of claim 6, in which the reaction is carried out in the presence of an acid binding agent, preferably an alkali metal hydroxide, carbonate or hydrocarbonate.
16. A process for sweetening a foodstuff or a pharmaceu-tical, in which said foodstuff or pharmaceutical is admixed with a compound of claim 1 of the general formula (I) or a salt thereof.
17. A process as claimed in claim 16, in which a salt, preferably the sodium, potassium or ammonium salt of 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-propanone-1 is added to said foodstuff or pharmaceutical.
18. A process as claimed in claim 16, in which a salt, preferably the sodium, potassium or ammonium salt of 1-(2-hydroxy-4-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-ethoxy-phenyl)-propanone-1 is added to said foodstuff or pharmaceutical.
19. A process as claimed in claim 16, in which a salt, preferably the sodium, potassium or ammonium salt of 1-(2-hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-propanone-1 is added to said foodstuff or pharmaceutical.
20. A process as claimed in claim 16, in which a salt, preferably the sodium, potassium or ammonium salt of 1-(2-hydroxy-5-/3-sulfo-propyl-1-oxy/-phenyl)-3-(3-hydroxy-4-ethoxy-phenyl)-propanone-1 is added to said foodstuff or pharmaceutical.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUCI1448A HU168495B (en) | 1974-02-19 | 1974-02-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1037491A true CA1037491A (en) | 1978-08-29 |
Family
ID=10994507
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA220,317A Expired CA1037491A (en) | 1974-02-19 | 1975-02-18 | Acyl-phenoxy-propanesulfoacids and salts, and artificial sweetening compositions containing the same |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS50116458A (en) |
| AT (1) | AT335999B (en) |
| CA (1) | CA1037491A (en) |
| CH (3) | CH605708A5 (en) |
| CS (1) | CS178037B1 (en) |
| DD (1) | DD119418A2 (en) |
| DE (1) | DE2506356C2 (en) |
| DK (1) | DK59375A (en) |
| ES (1) | ES434823A1 (en) |
| FI (1) | FI61306C (en) |
| FR (1) | FR2261262B2 (en) |
| GB (1) | GB1477283A (en) |
| HU (1) | HU168495B (en) |
| IL (1) | IL46633A (en) |
| IN (1) | IN143403B (en) |
| NL (1) | NL7501886A (en) |
| NO (1) | NO139919C (en) |
| PL (2) | PL95617B1 (en) |
| SE (1) | SE416728B (en) |
| SU (1) | SU584764A3 (en) |
| YU (1) | YU40257B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4025535A (en) * | 1975-03-24 | 1977-05-24 | Dynapol Corporation | Sulfoalkylated flavanone sweeteners |
| GB2010826A (en) * | 1977-12-22 | 1979-07-04 | Dynapol Corp | Improvements in and relating to sweeteners |
| KR0139296B1 (en) * | 1988-11-21 | 1998-05-15 | 가와무라 시게꾸니 | Chalcone derivatives and process for producing the same |
| PL2353403T3 (en) * | 2010-02-01 | 2012-10-31 | Symrise Ag | Use of 1-(2,4-dihydroxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-propan-1-on |
-
1972
- 1972-12-13 ES ES0434823A patent/ES434823A1/en not_active Expired
-
1974
- 1974-02-19 HU HUCI1448A patent/HU168495B/hu unknown
-
1975
- 1975-02-14 DE DE2506356A patent/DE2506356C2/en not_active Expired
- 1975-02-14 AT AT109575A patent/AT335999B/en not_active IP Right Cessation
- 1975-02-14 IL IL46633A patent/IL46633A/en unknown
- 1975-02-17 FR FR7504840A patent/FR2261262B2/fr not_active Expired
- 1975-02-17 DD DD184261A patent/DD119418A2/xx unknown
- 1975-02-18 CS CS1045A patent/CS178037B1/cs unknown
- 1975-02-18 SU SU7502108051A patent/SU584764A3/en active
- 1975-02-18 CH CH197575A patent/CH605708A5/xx not_active IP Right Cessation
- 1975-02-18 CA CA220,317A patent/CA1037491A/en not_active Expired
- 1975-02-18 NO NO750530A patent/NO139919C/en unknown
- 1975-02-18 NL NL7501886A patent/NL7501886A/en not_active Application Discontinuation
- 1975-02-18 DK DK59375*#A patent/DK59375A/da not_active Application Discontinuation
- 1975-02-18 PL PL1975178141A patent/PL95617B1/en unknown
- 1975-02-18 GB GB686375A patent/GB1477283A/en not_active Expired
- 1975-02-18 CH CH1600677A patent/CH613099A5/en not_active IP Right Cessation
- 1975-02-18 SE SE7501800A patent/SE416728B/en not_active IP Right Cessation
- 1975-02-18 YU YU374/75A patent/YU40257B/en unknown
- 1975-02-18 PL PL1975187792A patent/PL99700B1/en unknown
- 1975-02-18 FI FI750442A patent/FI61306C/en not_active IP Right Cessation
- 1975-02-19 IN IN318/CAL/1975A patent/IN143403B/en unknown
- 1975-02-19 JP JP50020801A patent/JPS50116458A/ja active Pending
-
1977
- 1977-10-14 CH CH1259277A patent/CH615326A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH615326A5 (en) | 1980-01-31 |
| DK59375A (en) | 1975-10-27 |
| NO139919C (en) | 1979-06-06 |
| FR2261262A2 (en) | 1975-09-12 |
| SE7501800L (en) | 1975-08-20 |
| NO750530L (en) | 1975-08-20 |
| ES434823A1 (en) | 1977-04-01 |
| NO139919B (en) | 1979-02-26 |
| FR2261262B2 (en) | 1978-08-18 |
| CS178037B1 (en) | 1977-08-31 |
| PL95617B1 (en) | 1977-10-31 |
| FI61306B (en) | 1982-03-31 |
| FI750442A (en) | 1975-08-20 |
| CH613099A5 (en) | 1979-09-14 |
| DE2506356A1 (en) | 1975-08-21 |
| YU37475A (en) | 1982-02-28 |
| NL7501886A (en) | 1975-08-21 |
| FI61306C (en) | 1982-07-12 |
| AT335999B (en) | 1977-04-12 |
| DE2506356C2 (en) | 1983-09-15 |
| IL46633A (en) | 1977-11-30 |
| SU584764A3 (en) | 1977-12-15 |
| DD119418A2 (en) | 1976-04-20 |
| IN143403B (en) | 1977-11-19 |
| YU40257B (en) | 1985-10-31 |
| PL99700B1 (en) | 1978-08-31 |
| CH605708A5 (en) | 1978-10-13 |
| ATA109575A (en) | 1976-08-15 |
| SE416728B (en) | 1981-02-02 |
| GB1477283A (en) | 1977-06-22 |
| HU168495B (en) | 1976-05-28 |
| JPS50116458A (en) | 1975-09-11 |
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