NO171410B - ASCORBIC ACID EETERS AND ANTI-ANXIOUS FOOD PREPARATIONS CONTAINING SUCH COMPOUNDS - Google Patents

Description

The present invention relates to ascorbic acid derivatives and antioxidant preparations for foodstuffs containing such compounds.

Ascorbic acid has anti-oxidation activity, and is used in foods to prevent them from turning brown, to retain the taste, to preserve freshness and the like.

However, ascorbic acid is prone to breakdown, and will in some cases have difficulties in producing the above-mentioned effects over a longer period of time.

Under these circumstances, extensive research has now been carried out in order to be able to produce an ascorbic acid derivative which is less susceptible to degradation and which also has satisfactory and antioxidant properties, and as a result of these investigations, it has been found that a modification of the 2-position in ascorbic acid with a relatively large molecular weight, can give a compound where the desired purpose is achieved. The present invention is based on this discovery.

According to the present invention, an ascorbic acid derivative is provided which is characterized by the formula:

wherein R 1 is (i) a C 5-22 alkyl or branched alkyl group; (ii) a C 1-10 straight or branched alkyl group having a substituent in the class consisting of (1) C^_^, alkoxycarbonyl groups, and (2) 2,3-dimethoxy-5-methyl-1,4-benzoquinoyl ; (iii) a ^2-2o> alkenyl group which may have one to two substituents in the class consisting of phenyl group and 3-pyridyl group; (iv) phenyl or naphthyl; (v) a morpholino carbonyl group; (vi) a C 1-3 alkoxy carbonyl pyrrolidino carbonyl group and

(vii) a C 1-3 alkoxy carbonyl group.

Furthermore, according to the invention, an antioxidant preparation for foodstuffs is provided, and this preparation is characterized by the fact that it contains at least one of the compounds of formula (I) as defined above.

The ascorbic acid derivative (I) can be prepared by hydrolysing and/or reducing a 5,6-acetal or ketal derivative (II) of a compound (III) with the following formula:

where ~ Ri is as defined above, and R 2 is a group which can be removed by hydrolysis or reduction.

The above-mentioned straight chain or branched alkyl groups have a molecular weight of from 58 to 400 and are those having from 5 to 22 carbon atoms, preferably those having from 9 to 20 carbon atoms.

Examples of such alkyl groups include, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl , n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, n-heneicosyl and n-docosyl.

The alkyl group in the above-mentioned straight-chain or branched alkyl groups with a molecular weight of 58 to 400 having one or more of the aforementioned substituents are preferably those having 1 to 10 carbon atoms.

Examples of said alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n -decyl.

Examples of the alkoxy group in said C 1-4 alkoxycarbonyl groups are, for example, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy and n-hexoxy.

Examples of said C2-20 alkenyl group are vinyl, propenyl, butenyl, penetenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl and eicosenyl, and the aryl substituent for such alkenyl groups are, for example, phenyl, naphthyl etc.

In the above-mentioned formula, the group which can be removed by means of hydrolysis or a reduction and which is indicated by R2" for example includes methoxymethyl, benzyloxymethyl, 2-tetrahydropropanyl, trimethylsilyl, dimethyl-tert-butylsilyl, benzyl and p-methoxybenzyl.

The above-mentioned acetal group includes, for example, groups with the following formula:

where R 3 is hydrogen, methyl, phenyl, p-methoxyphenyl, etc, while

the ketal group, for example, includes groups with the following formula:

where R4 and R5 can be the same or different, and each represents hydrogen, methyl or ethyl, or R4 and R5 can together form -(CH2)a-, where a is 4 or 5.

The compounds of formula (I) according to the present invention can, as mentioned, be prepared by subjecting a compound of formula (II) to hydrolysis and/or reduction.

In the case that one has a compound of formula (II) where the protecting group R2 in the 3-position is a group (for example methoxymethyl, benzyloxymethyl, trimethylsilyl, dimethyl-tert-butylsilyl), which can be removed by a hydrolysis reaction, then the elimination of this group in the 3-position and the removal of the acetal or ketal group in the 5- and 6-position can be carried out simultaneously by subjecting the compound of formula II to a hydrolysis reaction, whereby a compound of formula I is produced.

In the case where one has a compound of formula II where the protecting group R2 in the 3-position is a group

(eg 2-tetrahydropyranyl, benzyl, p-methoxybenzyl)

which can be removed by a reduction, the acetal or ketal group in the 5- and 6-position can first be removed by hydrolyzing the compound of formula II to the compounds of formula III, after which the said protecting group can be removed by reducing the compound, giving the compounds with formula I.

The above-mentioned hydrolysis is carried out by contacting the starting compound with an acidic catalyst. Examples of such catalysts include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, perchloric acid and acetic acid. This reaction is carried out in an aqueous solvent, and as such you can, for example, use methanol, ethanol, dioxane, 1,2-methoxyethane and tetrahydrofuran. The reaction temperature is chosen in the range from 0 to 80. The reaction time is from 10 min to 3 hours.

The above-mentioned reduction includes, for example, catalytic reduction. This is carried out by bringing the starting compound into contact with a catalyst. For example, palladium, palladium-carbon, platinum black and platinum dioxide can be used as said catalyst. This reaction is normally carried out in a solvent. As such, you can use, for example, methanol, ethanol, acetic acid and ethyl acetate. The reaction temperature is from 10°C to 40°C, and the reaction time from 1 to 18 hours.

The thus produced ascorbic acid derivative (I) can be separated and collected by separation and purification methods which are known per se (see for example column chromatography using polystyrene resin, activated carbon, reverse phase systems etc, recrystallization etc).

The compounds of formula (II) which are used as starting compounds can, for example, be prepared by the reaction steps shown below.

In the above forms, X is an acetal or ketal residue.

The above reaction, which includes the acetalization or ketalization of ascorbic acid to thereby produce the compound of formula (V), is carried out by reacting ascorbic acid with a ketone or aldehyde, such as acetone, benzaldehyde, cyclopentanone or cyclohexanone. For example, tetrahydrofuran, chloroform, diethyl ether, dichloromethane and dichloroethane can be used as solvents. The reaction temperature can vary from room temperature to 60°C, and the reaction should preferably be carried out in the presence of an acid catalyst. As said catalyst, rna can for example use sulfuric acid, p-toluenesulfonic acid and camphorsulfonic acid. The reaction time is from 4 to 24 hours.

Then the compound with (V) is reacted with a compound (for example chloroethyl methyl ether, benzyl chloride, benzyl bromide etc) with the formula R2-Y (where R2 is as defined previously, Y is halogen as for example chlorine, bromine etc), in dimethylformamide, dimethylsulfoxide , hexamethylphosphoramide or tetrahydrofuran, either individually or in a mixture of solvents, in the presence of an inorganic base, for example potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or sodium hydrogen carbonate, whereby the compound of formula (IV) is prepared. The reaction is carried out at temperatures between 0°C and 40°C (preferably 25°C), and the reaction time is from 1 to 18 hours.

The compound with (IV) can then be reacted with a compound of formula R1-CH2-Z (where R^ is as defined previously, Z is halogen (for example chlorine, bromine, etc)) in a solvent such as dimethylformamide, dimethylsulfoxide , hexamethylphosphoramide and tetrahydrofuran, either individually or as a mixture of solvents, in the presence of an inorganic base (for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc) with temperatures from 10° C to 60° C, for a period of time from 1 to 18 hours, giving a compound of formula (II).

The compounds of formula (II) or (III) prepared as indicated above can, as mentioned, be used as intermediates for the preparation of the present compound of formula (I).

The compound of formula (I) which has antioxidant properties and which also has an LD50 value of 0.8 to 10 g/kg body weight when given orally to mice, thus has very low toxicity, can be used as an antioxidant in foodstuffs.

The use of the compound of formula (I) as an antioxidant in foodstuffs is carried out by processing the compound into an antioxidant preparation for foodstuffs containing compounds of formula (I), after which this preparation is either added to or contacted with the food product.

When processing into a preparation, for example, the compound of formula (I) can be used as such without dilution, or with the help of known methods it can be processed to a suitable for or dilution.

If dilution is used, for example a carrier or diluent such as lactose, starch, etc. can be mixed with the compound (I), after which the mixture can be processed into the powder or granules by methods which are known in themselves.

Foodstuffs, to which antioxidant preparations according to the present invention are to be added, include, for example, fruit juice, fruit, edible meat products, fish, shellfish, in addition to oil and fat (for example salad oil, lard oil, etc.).

When using the antioxidant preparation according to the present invention, when the compound (I), its active ingredient, when it is soluble in water, then the powdered antioxidant preparation for dissolution thereof can be added to the foods directly, for example a fruit juice, various types or edible meat products, or you can dissolve the antioxidant preparation according to the present invention beforehand in water, after which the resulting solution is added to the fruit juice, fruit or edible meat products, or fish and fish products and shellfish can be put into said solution.

The present antioxidant preparation can, when it is to be used in edible meat products, fish and shellfish and the like, be processed into an aqueous emulsion using an aqueous emulsifier.

When the compound of formula (I), i.e. the active ingredient, is soluble in oil, the antioxidant preparation can be added directly to the oil and fat.

The amount used of the present antioxidant preparation for compounds of formula (I) will be from 0.02 to 0.04% (weight/weight) in connection with fruit juices and fruit; from 0.02 to 0.08 5É (w/w) in connection with edible meat products; $0.02 to $0.08 > (wt/wt) in connection with addition to fish and shellfish; and from 0.1 to 1% (w/w) as concentration in a solution to be prepared for immersion of the product; and from 0.002 to 0.02% (w/w) in connection with oils and fats.

Furthermore, the compound (I) can also be used as a bleaching agent in cosmetics. The amount used of the present compound as a bleaching agent in cosmetics will, for example, be from 0.1 to 1% (w/w) in connection with a moisturizing water, and from 0.1 to 1% (w/w) in connection with creams.

The following experimental examples, reference examples and examples described in the following illustrate the present invention in more detail.

EXPERIMENT 1

Antioxidant activity was determined by means of a stable radical: In accordance with the method of Brois MS (Nature, 181, 1199, 1958), the reducing activity of α,α-diphenyl-β-picrylhydrazyl (DPPH) was determined and this was used as a scale for the oxidation-inhibiting activity A compound that one wishes to test (for example compound (I) where R^ = - (CH2)i6CH3) added 3 ml of 0.1 mM DPPH ethanol soluble, and 20 minutes later the absorbance measured at a wavelength of 517 nm using a spectrophotometer, and the difference in absorbance from the solvent (not more than 0.5 56 DMF), as a measure of the reducing activity.

The results of the experiment are shown in figure 1.

In Figure 1, - - indicates the results using the above chemical compound, - - the results with vitamin E while - - are the results with vitamin C.

it was found that the above compound reduced DPPH at a concentration of more than 10"^ molar in an amount dependent manner. Vitamins C and E showed an activity similar to that found for the test compound.

EXPERIMENT 2

Sardines, after removing the guts and bones, were ground, and the ground sardines were without addition and with the addition of an amount of 0.03% and 0.05% of the compound of formula (I) where R]^ is ( CH2)4CH3 used to make fish balls. These were preserved by freezing at -20°C, and the peroxy value (POV) was measured in relation to the storage time.

The results are shown in table 1

EXPERIMENT 3

In a Petri dish with a diameter of about 10 cm was placed 25 g of salad oil, which had been stored in a thermostat at 60°C without addition, and with the addition of 0.03% and 0.05 # of the compound of formula (I) , where R^ = (CH2)i6CB3, after which the peroxy value (POV) was measured in relation to the storage time.

The results are shown in table 2

REFERENCE EXAMPLE 1

1) 21.6 g of 0.1 mol L-ascorbic acid acetonide was dissolved in 210 ml of dlmethylformamide, and the solution was cooled with ice. To the solution was added 14 g of 0.1 mol of potassium carbonate, and then 11.2 ml of benzyl bromide and then stirred at room temperature for 20 hours. After the reaction was complete, 100 ml of water was added, and the mixture was neutralized with 2N hydrochloric acid to a pH of 5.0, after which the mixture was extracted with 2 parts of ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The concentrate was chromatographed with a silica gel column, and elution was carried out with isopropyl ether-ethyl acetate (3:1). The eluate was concentrated, and the residue was recrystallized from the isopropyl ether-ethyl acetate, which gave 13 g of L-5,6-0,0-isopropyldiene-3-0-benzylascorbic acid (40#), mp 105 m-106°C. 2) 3.06 g of 0.01 mol of L-5,60,0-isopropyldiene-3-0-benzyl-ascorbic acid was dissolved in a mixture of 20 ml of dimethylformamide and 15 ml of tetrahydrofuran, after which 1.5 g of 0.011 mol of potassium carbonate was added to the solution. 3.83 g of octadecyl iodide were then added, and the mixture was stirred at room temperature for 18 hours. 100 ml of water was added and the reaction mixture was extracted with ethyl acetate. The organic layers were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and then the column was eluted with isopropyl ether-ethyl acetate (10:1), which gave 3.8 g of L-5,60,0-isopropylidene-3-0-benzyl-2-0-octa- decylascorbic acid, melting point 44-45°C.

Nuclear magnetic resonance spectrum CDCI3, internal standard: TMS, S value.

7.29 (5H,s), 5.43 (2H,s), 4.51 (lH,d,2Hz), 4.08 (3H,m), 1.38 (6E,s), 1.26 (32H,m), 0.88 (3H,t).

REFERENCE EXAMPLE 2

1) 42 g of 0.19 mol of L-ascorbic acid acetonide was dissolved in a mixture of 100 ml of dimethylformamide and 100 ml of kesamethyl phosphoramide, after which 32 g of 0.23 mol of potassium carbonate was added to the solution, which was then ice-cooled. A solution of 18 g of 0.22 mol of chloromethyl methyl ether in 25 ml of tetrahydrofuran was then added dropwise over the course of 20 minutes. After stirring at room temperature for 2 hours, 100 ml of water was added, after which 2N hydrochloric acid was used to adjust the pH to 5.0, after which the mixture was extracted with 4 portions of ethyl acetate. The organic layer was washed with water, dried and then concentrated under reduced pressure, after which the residue was chromatographed on a silica gel column, and then this was eluted with isopropyl ether-ethyl acetate (2:1). The eluate was concentrated and the residue recrystallized from the same solvent system to give 46 g or L-5,6-0,0-isopropyldiene-3-0-methoxymethylascorbic acid, mp 93-94°C.

Elemental analysis for CnEi^ Oj

Found: C, 50.84; B, 6.05

Calculated: C. 50.77; H, 6.20.

2) 1.84 g of 7.1 mol L-5,6-0,0-isopropylidene-3-0-methoxy-methylascorbic acid was dissolved in 10 ml of dimethylsulfoxide, after which 10 ml of octadecyl iodide and 1.0 g of potassium carbonate were added, after which the reaction mixture was kept at 60°C for 6 hours. 50 ml of water was then added, after which the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, after which the residue was chromatographed on a silica gel column which was then eluted with isopropyl ether. The eluate was concentrated, the residue was recrystallized with isopropyl ether-ethyl acetate, which gave 0.8 g of L-5,6-0,0-isopropylidene-3-0-methoxymethyl-2-0-octadecylascorbic acid, m.p. 50 - 52°C .

Nuclear magnetic resonance spectrum CDCI3, internal standard: TMS<*>, S value. ;5,-42.(2E,s), 4.53(1H,d,2Hz), 4.10(5H,m), 3.51(3E,s), 1.38(3H,s), 1.36(3H,s), 1.27(32H,m), 0.88(3H,t). ;<*> TMS: tetramethylsilane.

Reference example 3

By means of the same method as described in reference example 1 or 2, the compounds shown in the following table were prepared (where the compounds are indicated in formula II where R 1 and R 2 are as indicated in the table).

Example 1

1.2 g of L-5,6-0,0-isopropylidene-3-0-methoxymethyl-2-0-octadecyl-ascorbic acid was dissolved in 1 30 ml of methanol and 10 ml of tetrahydrofuran, after which 10 ml of 2N hydrochloric acid was added to the solution and this was then stirred at 50° for 6 hours. It was concentrated under reduced pressure, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure, after which the residue was recrystallized from isopropyl ether-ethyl acetate which gave 0.82 g of 1-0-octadecyl-ascorbic acid with melting point 127-128°C.

Nuclear magnetic resonance spectrum:

(CDC13, internal standard: TMS, S value)

4.69(1H,d), 3.88(3H,m), 3.53(2H,m), 1.25(32H,m),

0.87(3H,t).

Example 2

3.8 g of L-5,6-0,0-isopropylidene-3-0-benzyl-2-0-octadecyl-ascorbic acid was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of methanol, after which 20 ml of 2N hydrochloric acid was added the solution which was then stirred at 50° for 24 hours. Then it was concentrated under reduced pressure, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried and then concentrated under reduced pressure, after which the residue was recrystallized from isopropyl ether - ethyl acetate, which gave 2.6g of 3-0-benzyl-2-0-octadecylascorbic acid, melting point 75 - 76°C .

Nuclear magnetic resonance spectrum:

(CDCI3, internal standard, TMS, S value)

7.32(5E,s), 5.54(2H,s), 4.66(1H,d), 4.00(5H,m),

1.26(32H,m), 0.87(3H,t).

Example 3

Using the same method as described in example 2, the compounds shown in the following were prepared. In the table, the manufactured compounds are shown by the structural formula as represented by the formula

III.

Example 4

2.1 g of 3-O-benzyl-2-0-octadecylascorbic acid was dissolved in 25 ml of ethyl acetate, after which 0.5 g of 556 Pd-C was added to the solution to perform a catalytic reduction at atmospheric pressure. The catalyst was filtered off, and the filtrate concentrated under reduced pressure. The reaction product was recrystallized from isopropyl ether-ethyl acetate, yielding 1.5 g of 2-O-octadecyl ascorbic acid.

Melting point 127 - 128°C. _

NMR spectrum (d6-DMSO): 4.69(1H,d), 3.88(3H,m), 3.53(2H,m),

1.25(32H,m), 0.87(3H,"t).

Example 5

By means of the same method as described in example 1 or 4, the compounds indicated in the following were prepared.

In the following table, the prepared compounds have a structural formula represented by formula I.

Compounds 4 to 15 were prepared using the same procedures as described in Examples 2 and 3, and then oxidizing the resulting hydroquinone derivatives with ferric chloride.

Example 6

In a micromixer (Takara Koki Co., Ltd., Japan) 1.5 kg of the compound of formula I, where R-^ = -COOCH3 prepared as described in examples 5 - 12, 1.5 kg, was mixed for about 2 minutes the carrageenan and 1.5 kg of dextrin to reduce the mixture to a powder.

Mackerel was immersed in a solution of 15 g of the above-mentioned powder in 1 liter of water for 10 seconds, laid down to drain water and then preserved at -20°C for 6 months. This product was less rancid and had better color and gloss than compared to an untreated control.

Example 7

In a micromixer (manufactured by Takari Koki Co., Ltd., Japan) 3 kg of the compound of formula I where Ri = COOCH3 prepared as in examples 5 - 12 and 2 kg of dextrin were mixed for about 2 minutes to produce a powder .

A brine was prepared by dissolving 900 g of sodium chloride, 3 g of sodium sulphite, 150 g of sodium polyphosphate, 50 g of sodium L-glutamate, 120 g of sugar, 300 g of powdered egg white, and 30 g of a spice in 8.2 kg of ice-cold water (control) or 30 g of the above-mentioned powder (present invention). 300 g of each of the aforementioned salt solutions were injected into 1 kg pieces of ham respectively, and after rolling for 18 hours, the hams were filled in air-permeable casings, dried at 60° C for 30 minutes, smoked at 60° C for 1/2 hour and then steam cooked at 75°C for 1 hour to produce cooked and smoked ham.

The products were stored at 5°C overnight, cut open and placed in a room under diffused light for 3 hours and then examined for appearance, and it was found that the ham processed with a compound of the present invention had a red appearance and showed less discoloration, and was consequently better, than compared to the control.

Example 8

In a mixer, 700 g of the compound of formula I where R 1 = -(CH 2 ) i 6 CH 3 was prepared as described in example 1, was mixed with 300 g of cotton seed lettuce oil, thereby producing an oil solution.

700g of lean pork, 300g of lard, 10g of sodium chloride, 5g of sodium L-glutamate and 3g of spices were mixed, and the mixture was divided into 100g portions to make meat pies. Furthermore, the above mixture was also mixed with 0.8 g of the above oil solution, and the meat pies were prepared in exactly the same way. After deep freezing at -20°C for 3 months, the meat pies added to the oil solution had a less rancid taste than the control pies.

Claims (3)

1. Ascorbic acid derivative, characterized by the formula: wherein R 1 is (i) a C 5-22 straight or branched alkyl group; (ii) a C 1-8 straight or branched alkyl group having a substituent in the class consisting of (1) C 1-6 , alkoxycarbonyl groups, and (2) 2,3-dimethoxy-5-methyl-1,4-benzoquinoyl; (iii) a C2-20 alkenyl group which may have one to two substituents in the class consisting of phenyl group and 3-pyridyl group; (iv) phenyl or naphthyl; (v) a morpholino carbonyl group; (vi) a C 1-3 alkoxy carbonyl pyrrolidino carbonyl group and (vii) a C 1-3 alkoxy carbonyl group. 2. Compound according to claim 1, characterized in that Ri is -(CE^ifcC^. 3. Antioxidant preparation for foodstuffs, characterized in that it contains at least one of the compounds as defined in claim 1.