KR100533304B1 - Polyethoxylated alpha tocopherol ester derivatives and process for preparing the same - Google Patents

Abstract

The present invention relates to a novel polyethoxylated alpha tocopherol ester derivative represented by the following general formula (1) useful as an animal feed additive and a method for preparing the same:

[Formula 1]

Where

R is CH ₃ OCH ₂ CH ₂ (OCH ₂ CH ₂ ) n, where n is an integer from 2 to 400.

Description

Polyethoxylated alpha tocopherol ester derivatives and process for preparing the same}

The present invention relates to novel polyethoxylated alpha tocopherol ester derivatives and methods for their preparation. Polyethoxylated alpha tocopherol ester derivatives may be specifically referred to as DL-alpha-tocopheryl-ω-methoxypolyethyleneglycolyl-succinate derivatives.

Vitamin E (DL-alpha-tocopherol) represented by the following Chemical Formula 2 is widely used as an antioxidant in living organisms, and recently, the field of clinical application is expanding, and the demand for this is increasing:

[Formula 2]

Vitamin E is a compound having a hydroxy group in the benzene ring, which is physically insoluble in water, and because vitamin E itself is generally oxidized, it is not only chemically unstable but also an oxidation product of tocopherol quinone. Does not have the biological activity of vitamin E. Therefore, in order to prevent the oxidation of vitamin E is converted to more stabilized derivatives, such derivatives include tocopherol acetate, palmitate tocopherol, succinate tocopherol and the like. They have advantages of storage and transport because of their relatively high stability compared to vitamin E itself, and are effective for the manufacture of substitutes for vitamin E because of their acceptable stability for pharmacological purposes.

In addition, in the case of oral administration, the vitamin E ester compounds described above are completely hydrolyzed upon contact with pancreatic enzymes and intestinal enzymes when absorbed through the intestinal tract in vivo, and are absorbed in vivo in the form of tocopherols.

For this reason, vitamin E substitutes are widely used in all feedstocks, and tocopherol acetate is widely used as a source of vitamin E in pig feed, and it is widely known that it is effective as a meat improver of pork.

Accordingly, the present inventors have continued research to improve the chemical instability and the poor solubility in water, the most disadvantage of vitamin E mentioned above, and to develop a material that is more effective than tocopherol acetate, the poly according to the present invention Ethoxylated alpha tocopherol ester derivatives were found to be highly soluble in water, poorly oxidized and chemically stable. In addition, as a result of comparing efficacy of the above compound with tocopherol acetate, which is currently widely used as a source of vitamin E in pig feed, it has been newly found that not only meat improvement but also an increase effect of pork is completed.

It is therefore an object of the present invention to provide novel polyethoxylated alpha tocopherol ester derivatives and methods for their preparation.

The polyethoxylated alpha tocopherol ester derivatives of the present invention are represented by the following general formula (1):

[Formula 1]

Where

R is CH ₃ OCH ₂ CH ₂ (OCH ₂ CH ₂ ) n, where n is an integer from 2 to 400.

Preferred groups in the compound of Formula 1 are those having a group of R where n is an integer from 2 to 50.

Most preferred groups of compounds of formula (1) are DL-alpha-tocopheryl-ω-methyl polyethyleneglycoryl-succinate (n = 6); DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 11); DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 44).

The compound of Formula 1 includes all of the separated individual mixtures or single compounds. Also included in the scope of the invention are compounds that are radiolabeled to a compound of formula 1 suitable for biological research.

The compound of Formula 1 may be prepared by esterifying a compound of Formula 3 (DL-alpha-tocopherylsuccinate) with a compound of Formula 4:

[Formula 3]

[Formula 4]

R-OH

Wherein R is as defined above.

Specifically, the process of preparing the compound of formula 3 and compound of formula 4 in a suitable inert solvent such as methylenedichloride, acetonitrile, N, N-dimethylformaldehyde or toluene at room temperature, suitable condensing agents For example 1,3-dicyclohexylcarbodiimide (DCC) or paratoluenesulfonic acid and a suitable catalyst such as N, N-dimethyl-4-aminopyridine in the presence of tertiary amines.

The compound of formula 3 (DL-alpha-tocopheryl succinate) used as a starting material was prepared by treating alpha-tocopheryl with anhydrous succinic acid in N, N-dimethylformaldehyde and potassium hydroxide as organic reaction solvents. And already known materials.

Meanwhile, as the compound of formula 4 used in the present invention, polyethylene glycol methyl ether in which n is an integer of 2 to 400 may be mentioned, but polyethylene glycol methyl ether in which n is an integer of 2 to 50 is preferable.

In the reaction, the compound of Formula 4 is used in an amount of 0.8 to 2.0 equivalents, preferably 0.8 to 1.2 equivalents, based on the compound of Formula 3. The amount of the condensing agent is used based on the compound of Formula 3, 0.8 to 2.0 equivalents, preferably 0.9 to 1.5 equivalents. The amount of the catalyst used is 0.01 to 1.1 equivalents, preferably 0.1 to 1.0 equivalents based on the compound of formula (3). The reaction time is preferably about 5 hours.

The polyethoxylated alpha tocopherol ester derivative according to the present invention is a novel polyethoxylated alpha tocopherol ester compound covalently bonded to polyethylene glycol, which is a neutral polyether having physically and chemically diverse properties, and thus is an animal feed additive. Solubility in water is greater than that of tocopherol acetate, which is widely used as an additive, and especially when used as an additive in pig feed, it can be confirmed through experimental examples that explain not only meat improvement but also a gain effect.

Due to these characteristics, the compound according to the present invention is not only a very good compound as a vitamin E source of animal feed additives, but also maximizes the effect of feed with the use of low doses.

Therefore, the compound of formula 1 can be usefully used as a feed additive for animals.

Animal feed additives according to the present invention can be used as it is in a general feed or mixed with a general excipient that is acceptable for feed and then formulated and used in combination, the amount of the compound of formula 1 is based on the total weight of the feed vitamin The E concentration is usually 1 to 500 ppm and preferably 10 to 200 ppm.

The feed additive of the present invention is suitable for animal or fish feed as a vitamin E source. Specifically, the livestock includes cattle, horses, pigs, cows, sheep, goats, cats, dogs, mammals such as camels, animals with hair such as mink and chinchillas, animals in zoos and laboratory animals such as mice and rats; Birds such as geese, chickens, turkeys, ducks, pigeons, zoo birds and laboratory birds such as parrots and macaws; Fish such as carp, trout, salmon, tenches and eel, ornamental fish and aquarium fish; It is a reptile such as crocodile and snake.

The present invention is explained in more detail by the following examples and experimental examples, but the scope of the present invention is not limited in any way by these.

Example 1

Synthesis of DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 6)

DL-alpha-tocopherylsuccinate (5.3 g, 0,01 mole) was dissolved in methylene dichloride (20 ml) and then polyethylene glycol methyl ether (3.5 g, 0.01 mole, average molecular weight: 350, n = 6 ), 4- (dimethylaminopyridine (0.1 g, 0.001 mole) and dicyclo hexylcarbodiimide (2.7 g, 0.13 mole) are added and allowed to react for about 5 hours at room temperature. Washing with a 1N aqueous hydrochloric acid solution, drying with MgSO ₄ and removing the solvent under reduced pressure gave the title compound (7.7 g, 90% yield) as a liquid.

¹ H NMR (300MHz CDCl ₃ ): δ 0.82-0.89 (m, 12H), 1.08-1.74 (m, 26H), 1.98 (s, 3H), 2.03 (s, 3H), 2.09 (s, 3H), 2.57 (t, 2H), 2.78 (t, 2H), 2.94 (t, 2H), 3.38 (s, 3H), 3.56 ~ 3.60 (m, 26H), 4.29 (2H)

Molecular weight (M + 1) ⁺ : 855

Solubility (Water): 0.2% (wt%)

Example 2

Synthesis of DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 11)

Polyethylene glycol methyl ether (5.5 g, 0.01 mol, average molecular weight: 550, n = 11) was used instead of the polyethylene glycol methyl ether (3.5 g, 0.01 mol, average molecular weight: 350, n = 6) of Example 1. The title compound (9.8 g, yield 92%) was obtained using a liquid.

¹ H NMR (300 MHz CDCl ₃ ): δ 0.82-0.88 (m, 12H), 1.08-1.75 (m, 26H), 1.97 (s, 3H), 2.02 (s, 3H), 2.09 (s, 3H), 2.58 (t, 2H), 2.79 (t, 2H), 2.94 (t, 2H), 3.38 (s, 3H), 3.54-3.61 (m, 46H), 4.28 (t, 2H)

Molecular weight (M + 1) ⁺ : 1075

Solubility (Water): 0.3% (wt%)

Example 3

Synthesis of DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 44)

Polyethylene glycol methyl ether (20.0 g, 0.01 mol, average molecular weight: 2000, n = 44) was used instead of the polyethylene glycol methyl ether (3.5 g, 0.01 mol, average molecular weight: 350, n = 6) of Example 1. The title compound (25.3 g, yield 90%) was obtained.

¹ H NMR (300 MHz CDCl ₃ ): δ 0.82 to 0.99 (m, 2H), 1.08 to 1.76 (m, 26H), 1.96 (s, 3H), 2.01 (s, 3H), 2.08 (s, 3H), 2.56 (t, 2H), 2.78 (t, 2H), 2.93 (t, 2H), 3.37 (s, 3H), 3.45-3.76 (m, 178H), 4.27 (t, 2H)

Molecular weight (M + 1) ⁺ : 2527

Solubility (Water): 0.5% (wt%)

Experimental Example 1. Evaluation of the effect on the growth and carcass quality of finishing pigs

To examine the effect of the compound of formula 1 (compound prepared in Example 2, n = 11) compared to the standard control compound tocopherol on the growth and carcass quality of the finishing pigs when administered with the feed to the finishing pigs , Feed intake, weight gain per day, feed intake (feed intake / weight gain, lower values are more efficient) and carcass ratings were compared.

The total number of test animals was 160 (5 / pen), average weight 78 ± 2 kg (50 heads) 1 repetition, 74 ± 2 kg (50 heads) 2 repetitions, 70 ± 2 kg (50 heads) Three repetitions, the male and female ratio was adjusted to the same ratio so that there is no difference between treatments, the experiment was carried out using ternary hybrid pigs.

1. Experimental method

After weighing the subject's shaft, feed is fed for one week, followed by a week of purifying the struggle, then weighed again, and then fed test feeds.

In the case of the test feed, only the basic food and the vitamin-mineral mixture prepared with the energy protein of the hog test feed are purchased separately, but the vitamin E is purchased with the existing vitamin preparation. Compound 1 is supplied separately and used in feed formulations. Feed and water were allowed to be freely consumed, followed by a total of six weeks of specification testing, and body weight and feed requirements were measured every three weeks. Slaughter and graded at the end of the test.

2. Test result

TABLE 1

Effectiveness test results in pigs (n = 15 two)

density Weight (kg) Weight gain per day (kg / day) Feed Intake (kg) Feed requirement 0 weeks 3 weeks 6 Weeks 0 to 3 3 to 6 0-6 weeks 0 to 3 3 to 6 0-6 weeks 0 to 3 3 to 6 0-6 weeks Tocopherol Acetate 10 ppm 73.9 91.3 106.0 0.83 0.70 0.76 43.3 47.3 90.6 2.51 3.24 2.83 Tocopherol Acetate 90 ppm 71.7 88.2 103.4 0.79 0.73 0.76 42.2 48.0 90.2 2.58 3.18 2.85 Formula 110 ppm 70.8 88.9 104.8 0.86 0.76 0.81 43.4 49.2 92.6 2.42 3.20 2.73 Formula 190 ppm 71.5 90.2 106.8 0.89 0.79 0.84 45.7 52.5 98.2 2.45 3.19 2.78

TABLE 2

Conductor rating result (n = 15 two, average value)

Dosing method Live weight (kg) Conductor weight (kg) Conductor weight ratio (%) Back fat (mm) Conductor rating (%) A B C Tocopherol Acetate 104.3 79.0 75.9 19.5 48.9 42.2 8.9 Formula 1 106.3 80.1 75.4 18.5 53.3 42.2 4.4

The compound of the present invention can be used as a source of vitamin E in animal feed as can be seen in the above experimental example, and in particular, the effect of the meat improver of pork is superior to the conventionally widely used tocopherol acetate in pig feed, and when using tocopherol acetate It can be used as a source of vitamin E in all feeds because it can maximize the weight gain effect and feed requirements that were not expected.

Claims (4)

The polyethoxylated alpha tocopherol ester compound represented by the following formula (1): [Formula 1] Where R is CH ₃ OCH ₂ CH ₂ (OCH ₂ CH ₂ ) n, where n is an integer from 2 to 400. 2. A compound according to claim 1, wherein DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 6); DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 11); And DL-alpha-tocopheryl-ω-methyl polyethyleneglycolyl-succinate (n = 44). Esterification of the compound of formula 3 with the compound of formula 4 in the presence of a condensing agent selected from the group consisting of 1,3-dicyclohexylcarbodiimide, N, N-dimethyl-4-aminopyridine and paratoluenesulfonic acid A process for preparing the compound of formula 1 according to claim 1 comprising: [Formula 3] [Formula 4] R-OH Wherein R is as defined in claim 1. delete