IL46633A - 1-(sulfopropoxyphenyl)-3-(3-hydroxy-4-alkoxyphenyl)-propan-1-ones their preparation and artificial sweetening compositions containing them - Google Patents

Description

-4-io iNm»n-3)-3-('7,3D o iKS lis IE^ID)-! D n l K o»'7»Dan 0 » ·»η κ'·?ο npnon 1- (Sulfopropoxyphenyl)-3 - ( 3-hydroxy-4-alkoxyphenyl)propan-l-ones, their preparation and artificial sweetening compositions containing them I CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT. 4 C:- 44605 This invention relates to new acyl~pb.¾ noxy- ropane- 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. Although 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 seccharin-compositions are known in which the favourable sweetening ability of saccharin is utilized, and the unpleasant after-taste is attempted to be suppressed with sugar or other additives rich in calory. Thus, for instance, U.S. patent specification No, 3 > 74·3 ,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- cT-iactone , respectively, U.S. patent specification No. 5 , 087,821 describes hespere in-dihydrochalcon-glu-coside as a compound with intense sweet taste and applicable as artificial sweetener, and U.S. patent specification No. 3, 9 ,873 describes the preparation of these compounds from the hespere ine-like natural fle ononglucosides occurring in citruses. The extremely specific nature of sweet taste is reflexted by the fact that hesperetine-dihydrochalcon-rhu-tinoside is a tasteless substance, whereas the glucoside formed by splitting an L^rhamnose molecule from this compound has already a sweetening value equivalen to that of saccheri: The prepara ion of di ydro chalcon-alkoxycarboxylic acid derivatives and their salts is described in Hungarian patent specification No. 163,394·» This invention relates to novel acyl-phenoxy-pro ane-sulfoacids of the general formula (I), wherein "alkyl" stands for a G^_^ alb l group, and to the salts thereof.

These compounds are very well soluble, thermally stable, resistant to the action of acids, and non-toxic.

They have great sweetening values, and have no unpleasant by--flavour. Thus these compounds, optionally in combination with additives, indifferent salts or other sweetening agents, can be applied to great advantage for sweetening foodstoffs, pharmace ticals, etc. As additives, e.g. diluents, solvents, carriers, substances promoting the impressio of sweet 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.

The most preferred group of the new compounds having the general formula (I) includes the following substances: l-( 2-hydroxy- -/3-sulf o-prop: l-l-oxy/-phenyl ) -3- ( 3-hydroxy- -methoxyptienyl)-propane-l-o => and salts, 1_( 2-hydroxy- 3-sulf o-prop x-l-oxy/-phe uy 1 ) -3- ( 3-hyd oxy- 4-ethoxyphenyl)-propane-l-one and salts, | l-(2-hydroxy-5-/3-sulfo-propyl-l-oxy/-phenyl)-3- (3-hydroxy- - methoxy-phenyl)-propane-1-one and salts, l-(2-hydroxy-5-/3-sulfo-propyl-l-ox^/-phenyl)-3- (3-hydroxy ethoxyphenyl)-propane-1-one and salts.

As mentioned above, the invention also relates to a pro cess 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: compound of the general formula (II), wherein "alkyl" stands for a 01-Μ alkyl group, E stands for hydrogen or a protecting group capable to split off upon hydrogenolysis, such as benzyl or benzyloxy- carbonyl group, and M+ stands for" a proton or another cation, is reduced; or compound of the general formula (III), wherein "alkyl" has the same meanings as defined above, is reacted, optionally after protecting the phenolic hydroxy group attached to position 5 of the ring, with a compound of the general formula (IV), CHP - SO - i 2 2 (iv) CH2 - CH2 - I wherein X stands for a group of the genersl formula 0~M* and Y stands for halogen, or X and X represent together an oxygen atom; or c) group S1 of a compound of the general formula (V), wherein stands for a protecting group capable of splitting off in acidic media, such as 2-tetrahydropyranyl or 1-ethoxy-ethyl group, and M+ and "alkyl" each have the same meanings as defined above, is removed in an acidic medium; and, if desired, a compound o the general formula (I) is converted 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.

When Y stands for halogen, it may re resent prefer¬ ably chlorine , bromine or iodine.

In Method a) of ;he invention, a compound of the general formula (II) is .reduced preferably by catalytic hydrogenation. As catalyst, e.g. palladium, preferably supported e.g. on carbon, platinum, or Raney-nickel can be used.

The hydrogena ion is performed in a solvent, 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 dime thylformamide , or by fusing the reactents in the absence of solvent. In both instances an acid binding agen preferably an alkali metal hydroxide, carbonate or hydrocarbona e, is added to the reaction mixture. As the reactant of the general formula (IV), preferably propane suitone or a 5-halo-l-propanesulfonic acid, or a salt thereof can be used.

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 prepared as follows: The compounds of the general formula (II) can be prepared by condensing a salt of a sulfoacid of the formula H05S-CH2-CH2-CH2- (VI) with a compound of the general formula (VII), Oalkyl wherein R and "alkyl" each have the same meanings as defined above. The condensation is carried out at room temperature, in the presence of an aqueous solution of an alkali metal hydroxide, preferably sodium or potassium hydroxide. According to another method, the compounds of the general formula (II) can be prepared by reacting a compound of the general formula (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 bindin agent, such as an alkali metal hydroxide, carbonate or hydrocarbonate The compounds of the general formula (III), used as starting substances according to Method b) , can be prepared by reducing the corresponding compounds of the. general formula (VIII)· The reduction is performed preferably 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 can also be converted into salts formed with other metal ions. In this instance preferabl a poorly water-soluble salt of the acid of the general formula (I), such as the calcium salt, is prepared first, and then 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 Example s.

Sam le 1 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 mixture is heated cautiously until a homogeneous solution is obtained. The reaction mixture is cooled to 0°G; on cooling the salt of the acetophenone reactant separates. Propane sui one 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 0°C 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 mixture is cooled to 0°C, the separated product is filtered off, 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--(5-sulfo-propyl-l-oxy) -acetophenone sodium salt are obtained? m.p.: 500°C. j&cemple 2 A mixture of 5.0 g. of 2-hydroxy-4-( 3-sulfo-propyl- 1-oxy)-acetophenone sodium salt, 2.6 g. of isovanillin and 17 ml. of 8 N sodium hydroxide solution is stirred at room temperature for 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. 6.0 g. (82 %) of 2» ,3-dihydroxy-~methoxy--»-(5-sulf0-propyl-l-oxy)-chalcon sodium salt are obtained; m.p.: 273-276°C. If desired, this product can be purified further by recrystalliza ion from water.

Example 5 A mixture of 1 . g. of 2-hydroxy-4-(3-sulfo-propyl-1-oxy)_acetophenone sodium salt, 8.0 g. of 3-hydroxy-4-ethoxy-benzaldehyde and 60 ml. of a 8 I sodium hydroxide solution is stirred at room temperature for 96 hours. The yellow suspension is acidified with 10?S hydrochloric acid, the separated crude product is filtered off, and recrystallized twice from water. 6.0 g. (28 ) of 2S3-dihydroxy-4-ethoxy-4»-(3-sulfo-propyl-l-oxy)-chalcon sodium salt are obtained. The product shrinks at 250°C without melting.

Example 4 A solution of 5.0 g. of 2» ,3-dihydroxy-4-e thoxy-4»-(5-sulfo-propyl-l-oxy)-chaIcon sodium salt in 50 ml. of water is hydrogenated at 60°0, in the presence of 1 g. of palladium/carbon catalyst, until the uptake of the calculated amount of hydrogen. The mixture is filtered, the filtrate is evaporated to dryness, and the residue is recrystallized twice from minimum amount of water. 2.0 g. (40 %) of l-(2-hydroxy- -/J-su onyl-propyl-l-oxy/-phenyl>-3-(3-hydroxy-4-Gbhoxyphinyl)- propanone-1 ere obtained; m.p.: 239-2 1°U ( decompos iinm) . i¾xample ^ Δ solution of 20 g. of l-(2-hydroxy- -/3-sulfo-propyl- l-oxy/-phenyl)-3-( 3-hydrox3'- -methoxyphenyl) -prop-2-ene-l-one sodium salt in 100 ml. of water is hydrogenated at 60°C in the presence of g. of palladium/carbon until the uptake of the celouleted amount of hydrogen. The mixture is heated to 95°0, the catalyst is filtered off, end the filtrate is cooled. The separated substance is filtered off, washed with a few amount of ice water, and dried. 1 to 14 g. (65 to 70%) of l-(2-hydroxy-4-/3-s lfo-propyl-l-oxy/-phenyl) -3-( 3-hyaroxy- -me thoxyphenyl) -propsnone-1 are obtained; m.p.: 257-258°C (decomposition).

Example 6 10 g. of l-(2-hyuroxy- -/3-sulfo-propyl-l-oxy/-pbonyl)- 3-( 3-ben3yloxy- ~mc thoxyphenyl) -prop-2-ene-l-one are added to pre-hydrogensted palladium/cerbon catalyst in 50 ml. of water, and the obtained suspension is stirred at 60°G until the uptake of 2 molar equivalents of hydrogen. The solution is filtered when hot, and the filtrate is cooled. 7.0 g» of l-( 2-hydroxy-4-/3-sulfo-pro yl-l-oxy/-phenyl) -3- ( 3-hydroxy- -me hoxyphenyl) -pro snone-1 are obtained.

Example, 7 10 g. of l-(2-hydroxy- -/3-sulfo-l-propyl-l-oxy/-phenyl)-3-( 3-/2-tebrahydropyranyloxy/-4-methoxyphenyl) -prop-2-eno-lone are added to palladium/carbon catalyst pre-hydrogonc od in 50 ml. of water, and the obtained suspension is stirred at 60°G until the uptake of one molar equivalent 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 ^00G for 20 minutes. On cooling, 6.5 g. of l~(2-hydroxy~^/3-sulfo-propyl-l-oxy/-phenyl)-3-(3-l¾rdroxy-^ me hoxyphenyl)-propanone-l separate from the solution.

Plxample 8 7.2 g. of l-(2, --dihydroxyphenyl)-3-( -/2-te rahydro-pyranyloxy/- -methoxyphenyl)-propanone-l are dissolved in 22 ml. of a 1 N sodium hydroxide solution, and 2.63 g. of propanesultone are added to the solution in portions within one hour. The solutio is heated on a steam bath for 15 minutes, thereafter 2 ml. of concentrated hydrochloric acid are added, and heating is continued for additional 20 minutes. T e solution is filtered when hot, and the filtrate is cooled. 4.0 g. of l-(2-hydroxy-4-/3-sulfo-propyl-l-oxy/-phenyl) -3~ -(3-hydroxy-4-me hoxyphenyl)-propanone-l are obtained.

Example 9 The sodium salt of l-(2-hydroxy-4-/3-sulfo-propyl~l-oxy/-phenyl)-3-(3-hydroxy- -methoxyphenyl)-propanone-l con be converted into other salts via the poorly soluble calcium salt. An excess of a calcium chloride solution is added to the warm, concentrated aqueous solution of th& 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-haIf hours, the separated calcium sulfate is removed by filtration, and the filtrate is evaporated, or the obtained salt is allowed to crystallize, respectively.

Claims (2)

1. Wha we claim 1* A compound of the general formula (I), wherein "alkyl" stands for a alkyl group, or a salt thereof «, 2 » l-( 2-Hydxoxy- -/5-sulf o-propyl-l-oxy/-phenyl) - -5- (3- hydroxy— <4- me thoxyphenyl) -propanone-1 or its salts. J. l-( 2-Hydroxy-^/3-sulf o-propyl-l-oxy/- eιlyl)- ~3-(5-hydroxy- -«e thoxyphenyl) -propanone-1 or its salts 0 4. l-(2-Hydroxy-5-/5-sulf o-propyl-l-oxy/ -phenyl) - - -(3-hydroxy- — me thoxyphenyl) -propano&e-l or its salts. 5. l-( -Hydroxy-5-/3-sulf o~propyl-l-oxy/-phe yl) - _3_(3_hydroxy-4-e hoxyphenyl) -propa o e-1 or its salts. 6. A process for the preparation of a. new acyl- phenoxy-propanesulf oacid of the general formula (I), wherein "alkyl" stands for a C-^ alkyl. group, or a salt thereof, in which a) a compound of the general formula (II), wherein "alkyl1' stands for a G1__^ alkyl group, R stands for hydrogen or a protecting group capable to spli off upon hydrogenolysis, preferably a benzyl or benzyloxy- cerbonyl group, and M+ stands for a proton or another cation, is reduced; o b) a compound of the general formula (III), wherein "alkyl" has the same meanings as defined above, is reacted optionally after protecting the phenolic hydroxy group attached to position 5 of the ring, with a compound of the general formula (IV), wherein X stands for a group of the general formula 0~M+ and X stands for halogen, or X and Y represent together an oxygen atom? or «r) group R1 of a compound of the- general formula (V) s - 3A - wherein R stands for a protecting group capable of splitting off in acidic media, such as 2-te rahydro yrany1 or 1-e hoxy-ethyl 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,, 7o A process as claimed in variant b) of claim 6, in which the reactant of the general formula (IV) is propane- a sultone, 3-halo-l~pro anesulfoacid, or a salt thereof,, 8o A process as claimed in variant a) of claim 6, in which a compound of the general formula (II), prepared by reacting a salt of a compound of the formula (VI) wifch a compound of the general formula (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), 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 reduction is carried out by catalytic hydrogena-tion in the presence of platinum, palladium/carbon, Raney-nickel or palladium. 12. A process as claimed in claim 11, in which the catalytic hydrogenation is performed in a solvent, preferably in water, at or above room temperature. 15. A process as claimed in claim 11 or 12, in which the catalytic hydrogenation is performed under atmospheric or supera mospheric pressure. 14. A process as claimed in variant b) of claim 6, in which the reaction is carried out either at room tempera bwtT in the presence of a solvent, preferably water or dimeth 1-formemide, 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 hydrocarbons e<> 16„ A sweetening composition containing as main ingredient a compound of the general formula (I) or a salt thereofo · 17o A sweetening composition containing as main ingredient a compound of the general formula (I) or a salt thereof in an amount of at leastrO.Ol % by weight, together with a carrier or diluent, or optionally a further sweetener and/or a substance promoting the impression of sweet taste. 18o A process for sweetening a foodstuff or a pharmaceuticals in which said foodstuff or pharmaceutical is admixed with a compound of the. general formula (I) or a salt thereofo 19 o A process as claimed in claim 18, in whi6h a salt, preferably the sodium, potassium or ammonium salt of l-(2-hydroxy^/5-sulfo-propyl-l-oxy/-p enyl)-5-(3-hydroxy- -methoxyphenyl)-propanone-l is added to said foodstuff or pharmace tical 20o A process as claimed in claim 18, in which a salt, preferably the sodium, potassium or ammonium salt of 1- ( 2-hydroxy-4-/3-sulfo-propyl-l-oxy/~phenyl) ( 3-bydroxy-4~ethoxyphenyl)-propanone-l is added to said foodstuff or pharmaceuticalo 21. A process as claimed in claim 18, in which a salt, preferably the sodium, potassium or ammonium salt of l-( 2-hydroxy-5-/5-'sulfo-propyl-l-oxy/~phenyl) -3-(3-hydroxy- -methoxyphenyl)-propanone-l is added to said foodstuff or pharmaceutical. 22. A process as claimed in claim 18, in which a salt, preferably the sodium, potassium or ammonium salt- of l-( 2-hydroxy-5-/3-sulfo-propyl-l-oxy/-phenyl)-3- ( 3-hydroxy- -ethoxyphenyl)-propanone-l is added to said foodstuff or pharmaceutical, 3o A compound as claimed in claim 1, substantially as hereinbefore described, with special reference to the Examples.

2. , A process as claimed in claim 6, substantially as hereinbefore described with special reference to the Examples.