WO2016131202A1 - Robenidine series salt and application thereof in preparing growth promoter for animal feed - Google Patents

Abstract

Disclosed are a robenidine series salt and an application thereof in preparing a growth promoter for animal feed. The structural formula of the robenidine series salt is shown in formula (I): R is DL-lactic acid, methanesulfonic acid, 2-isethionic acid, citric acid, tartaric acid, benzoic acid, succinic acid, fumaric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid, or oxalic acid.

Description

Series of chlorpheniramine and its application in preparing animal feed growth promoter Technical field:

The invention belongs to the field of animal and animal animal feed, and particularly relates to a series of salts of chlorpheniramine and its application in preparing animal feed growth promoters.

Background technique:

Feed growth promoters include a variety of chemical structures of biologically active substances and their preparations, which play an important role in improving feed conversion ratio and improving livestock production efficiency. However, many antibiotic growth promoters have been or will be banned due to drug resistance problems.

Therefore, how to screen for safe and efficient feed growth promoters without human medical use and without cross-resistance with human antibiotics, especially non-antibiotic-based, non-hormone-type feed growth promoters is a problem. solved this problem.

Chloroquinone hydrochloride is traditionally an anticoccidial for animals.

Summary of the invention:

A first object of the present invention is to provide a series of salts of chlorophenyl hydrazine which are capable of promoting the growth of animals.

The series of salts of chlorophenylhydrazine of the present invention have a structural formula as shown in the formula (1):

Wherein: R is DL-lactic acid, methanesulfonic acid, 2-hydroxyethylsulfonic acid, citric acid, tartaric acid, benzoic acid, succinic acid, fumaric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid or oxalic acid.

A second object of the present invention is to provide a use of a series of salts of chlorophenylhydrazine represented by formula (1) for the preparation of an animal feed growth promoter.

The animals are farm animals such as ducks, pigs, and chickens at various stages of growth.

The series of salts of chlorpheniramine, wherein the amount of the additive in the animal feed is 0.1 to 1000 ppm. The feed described is a full-price compound feed.

The series of salts of chlorophenylhydrazine represented by formula (1) of the present invention are low-toxic or non-toxic to animals, and therefore are suitable as feed growth promoters, and have very good application prospects in the aquaculture industry.

In this study, it was found for the first time in the breeding experiment that the performance of the ducks was significantly improved after the application of the series of salt compounds of chlorpheniramine. In this study, it was also found through animal feeding experiments that the application of such a series of salt compounds of chlorophenyl hydrazine improves the production performance of pigs and chickens. Therefore, the series of salts of chlorpheniramine of the present invention can be used for preparing animal feed growth promoters. Has a broad market prospects.

detailed description:

The following examples are intended to further illustrate the invention and not to limit the invention.

The series of salts of chlorophenylhydrazine in the present invention have a specific structural formula as shown in the formula (1):

Wherein: R is DL-lactic acid, methanesulfonic acid, 2-hydroxyethylsulfonic acid, citric acid, tartaric acid, benzoic acid, succinic acid, fumaric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid or oxalic acid.

Preparation of free Robennidine/chlorophenylhydrazine

Add 45 g of p-chlorophenylhydrazine hydrochloride to 450 ml of 95% ethanol, add 6.5 g of KOH while stirring, add, continue stirring for 0.5 h, add 100 ml of water, continue stirring for 1-2 hours, suction filtration, filter cake with water It was washed to neutrality, and the obtained solid was dried at 45 ° C to obtain a product (chlorophenylhydrazine).

Preparation of chlorophenyl hydrazine.R salt

Wherein R is DL-lactic acid, methanesulfonic acid, 2-hydroxyethylsulfonic acid, citric acid, tartaric acid, benzoic acid, succinic acid, fumaric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid or oxalic acid.

Example 1: Preparation of Robennidine 2-hydroxypropanoic acid/chlorophenylhydrazine.DL-lactate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.4 g of DL-lactic acid, stir for 2 h, filter, filter cake washed with 95% ethanol, washed with water, and then dried at 45 ° C overnight to obtain the product (chlorobenzene)胍.DL-lactate). δH (DMSO, 500MHz) δ 8.043 (2H, s), δ 7.791-7.808 (4H, d), δ 7.420-7.437 (4H, d), δ 6.691 (2H, s), δ 4.011- 4.052 (1H, m), δ 1.225-1.239 (3H, d).

Example 2: Preparation of Robennidine.methanesulfonic acid/chlorophenylhydrazine.methanesulfonate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.4 g of methanesulfonic acid, stir for 2 h, filter, filter cake with 95% ethanol, wash with water, then dry at 45 ° C overnight to obtain the product (chlorobenzene胍.Methanesulfonate). δH (DMSO, 500 MHz) δ 12.098 (2H, s), δ 8.596 (2H, s), δ 8.355 (2H, s), δ 7.969-7.986 (4H, d), δ 7.550-7.567 ( 4H, d), δ2.430 (3H, s).

Example 3: Preparation of Robennidine. 2-hydroxyethanesulfonic acid/chlorophenylhydrazine. 2-hydroxyethylsulfonate

Take 1.4g of free chlorophenyl hydrazine, add 8ml of 95% ethanol, stir at room temperature, add 0.5g of isethionate, stir for 2h, filter, filter cake washed with 95% ethanol, washed with water, then dried at 45 ° C overnight to obtain the product ( Chlorobenzoquinone. 2-hydroxyethyl sulfonate). δH (DMSO, 500 MHz) δ 11.986 (2H, s), δ 8.559 (2H, s), δ 8.367 (2H, s), δ 7.968-7.985 (4H, d), δ 7.558-7.575 ( 4H,d), δ3.641-3.668(2H,m), δ2.650-2.676(2H,m).

Example 4: Preparation of Robennidine. 2-hydroxypropane-1,2,3-tricarboxylic acid/chlorophenylhydrazine. Citrate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.8 g of citric acid, stir for 2 h, filter, filter cake with 95% ethanol, wash with water, then dry at 45 ° C overnight to obtain 1.8 g of product (chlorine Benzoquinone. Citrate), yield 75%. δH (DMSO, 500 MHz) δ 10.969 (2H, s), δ 8.125 (2H, s), δ 7.837-7.854 (4H, d), δ 7.457-7.414 (4H, d), δ 7.182 ( 2H, s), δ 2.682-2.713 (2H, d), δ 2.591-2.622 (2H, d).

Example 5: Preparation of Robennidine.(2R,3S)-2,3-dihydroxysuccinic acid/chlorophenylhydrazine. Tartrate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.6 g of tartaric acid, stir for 2 h, filter, filter cake with 95% ethanol, wash with water, then dry at 45 ° C overnight to obtain the product (chlorophenyl hydrazine. tartaric acid salt). Chlorobenzoquinone: tartaric acid = 2:1. δH (DMSO, 500MHz) δ 8.069 (2H, s), δ 7.807-7.824 (4H, d), δ 7.431-7.448 (4H, d), δ 6.876 (2H, s), δ 4.223 ( 1H, s).

Example 6: Preparation of Robennidine.benzoic acid/chlorphenirium benzoate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.5 g of benzoic acid, stir for 2 h, filter, filter cake with 95% ethanol, wash with water, then dry at 45 ° C overnight to obtain product (chlorophenylhydrazine) . Benzoate). Chlorobenzoquinone: benzoic acid = 1:2. δH (DMSO, 500 MHz) δ 11.619 (1H, s), δ 8.018 (2H, s), δ 7.942-7.958 (4H, d), δ 7.780-7.797 (4H, d), δ 7.557- 7.572 (2H, m), δ 7.414-7.483 (8H, m), δ 6.570 (4H, s).

Example 7: Preparation of Robennidine.succinic/chlorophenylhydrazine.succinate

Take 1.4 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, stir at room temperature, add 0.28 g of succinic acid, stir for 2 h, filter, filter cake with 95% ethanol, wash with water, then dry at 45 ° C overnight to obtain the product (chlorophenylhydrazine) . succinate). δH (DMSO, 500MHz) δ11.966(2H, s), δ8.045(2H, s), δ7.792-7.809(4H,d), δ7.421-7.438(4H,d), δ6.707( 2H, s), δ2.415 (6H, s).

Example 8: Preparation of chlorophenyl hydrazine. Fumarate

1.6 g of free chlorophenyl hydrazine was added, 8 ml of 95% ethanol was added, and the mixture was stirred at room temperature, 0.28 g of fumaric acid was added, and the mixture was stirred overnight. Filtration, the filter cake was washed with 95% ethanol and then dried at 45 ° C overnight to give 1.78 g of product (chlorophenylhydrazine, fumarate) in a yield of 94.6%. δ ¹ H NMR (500 MHz, d-DMSO): δ 12.39 (br, 1H), δ 8.07 (s, 2H), δ 7.84 (d, 4H), δ 7.45 (d, 4H), δ 7. 09 (br, 2H), δ 6.62 (s, 1H).

Example 9: Preparation of chlorophenyl hydrazine. Maleate

1.6 g of free chlorophenyl hydrazine was added, 8 ml of 95% ethanol was added, and the mixture was stirred at room temperature, 0.28 g of maleic acid was added, and the mixture was stirred overnight. After filtration, the filter cake was washed with 95% ethanol and then dried at 45 ° C overnight to obtain 1.75 g of product (chlorophenylhydrazine, maleate), yield 93.2%. δ ¹ H NMR (500MHz, d-DMSO): δ 11.79 (br, 1H), δ 8.22 (s, 2H), δ 7.91 (d, 4H), δ 7.74 (br, 2H), δ 7. 51 (d, 4H), δ 6.03 (s, 1H).

Example 10: Preparation of chlorophenylhydrazine. Acetate

Take 1.6 g of free chlorophenyl hydrazine, add 8 ml of 95% ethanol, and stir at room temperature. 0.29 g of acetic acid was diluted with 2 ml of 95% ethanol, added dropwise to the reaction flask, stirred for 2 h, and filtered. The filter cake was washed with 95% ethanol, washed with water, and then dried overnight at 45 ° C to give 1.73 g of product (chlorophenylhydrazine acetate) in a yield of 91.7%. δ ¹ H NMR (500MHz, d-DMSO): δ 11.60 (br, 1H), δ 8.02 (s, 2H), δ 7.81 (d, 4H), δ 7.44 (d, 4H), δ 6. 77(br, 2H), δ1.91(s, 3H).

Example 11: Preparation of chlorophenyl hydrazine. Sulfate

1.6 g of free chlorophenyl hydrazine was added, 8 ml of 95% ethanol was added, and the mixture was stirred at room temperature, 0.24 g of sulfuric acid was added, and the mixture was stirred and dissolved. After stirring for 0.5 h, water was added to precipitate a solid, which was filtered, and the filter cake was washed with 95% ethanol, washed with water, and then dried at 45 ° C overnight to obtain 1.74 g of product (chlorophenylhydrazine. sulfate) in a yield of 94.8%. δ ¹ H NMR (500MHz, d-DMSO): δ 11.42 (br, 1H), δ 8.21 (s, 2H), δ 7.89 (d, 4H), δ 7.72 (br, 2H), δ 7. 50 (d, 4H).

Example 12: Preparation of chlorophenyl hydrazine. phosphate

1.6 g of free chlorophenyl hydrazine was added, 8 ml of 95% ethanol was added, and the mixture was stirred at room temperature, 0.16 g of phosphoric acid was added, and the mixture was stirred and dissolved. After stirring overnight, filtration, the filter cake was washed with 95% ethanol, washed with water, and then dried overnight at 45 ° C to obtain 1.03 g of product (chlorophenylhydrazine. phosphate) in a yield of 58.6%. δ ¹ H NMR (500 MHz, d-DMSO): δ 8.09 (s, 2H), δ 7.83 (d, 4H), δ 7.45 (d, 4H), δ 7.07 (br, 2H).

Example 13: Preparation of chlorophenyl hydrazine. Oxalate

1.6 g of free chlorophenyl hydrazine was added, 8 ml of 95% ethanol was added, and the mixture was stirred at room temperature, 0.22 g of oxalic acid was added, and the mixture was stirred overnight. After filtration, the filter cake was washed with 95% ethanol and then dried at 45 ° C overnight to give 1.73 g of product (chlorophenylhydrazine. oxalate) in a yield of 95.3%. δ ¹ H NMR (500MHz, d-DMSO): δ 8.16 (s, 2H), δ 7.87 (d, 4H), δ 7.46-7.49 (m, 6H).

Example 14: Effect of series of chlorpheniramine on production performance of broilers

1200 1 day old fast yellow broiler chickens were divided into 15 groups according to 80/group. In the same basic diet, different kinds of chlorpheniramine series salts were added. During the experiment, they were free to eat and drink, and fed for 30 days. , statistical production performance and survival rate (this test was carried out in cages sterilized by coccidia to ensure no coccidiosis infection). The grouping and dosage are shown in Table 1, and the production performance test results are shown in Table 2. From the test results, the effects of different chlorpheniramine series on the performance of broilers were different. Among them, chlorophenyl hydrazine DL-lactate and chlorpheniramine 2-hydroxyethyl sulfonate had the most obvious improvement on broiler performance. The effect is better than the hydrochloride, while the other salts are less effective than the hydrochloride.

Table 1 Comparison test group of effects of series of chlorpheniramine on performance of broilers

Group Number of test chickens (only) Compound Dose* (ppm) 1 80 - 0 2 80 Chlorobenzoquinone DL-lactate 50 3 80 Chlorobenzoquinone mesylate 50 4 80 Chlorobenzoquinone 2-hydroxyethyl sulfonate 50 5 80 Chlorobenzoquinone citrate 50 6 80 Chlorobenzoquinone tartrate 50 7 80 Chlorobenzoquinone benzoate 50 8 80 Chlorobenzoquinone succinate 50 9 80 Chlorobenzoquinone fumarate 50 10 80 Chlorobenzoquinone maleate 50 11 80 Chlorobenzoquinone acetate 50 12 80 Chlorobenzoquinone sulfate 50 13 80 Chlorobenzoquinone phosphate 50

14 80 Chlorobenzoic acid oxalate 50 15 80 Chloroquinone hydrochloride 50

*: The test dose is based on the chlorophenyl hydrazine dosage.

Table 2 Comparison test results of the effects of series of chlorpheniramine on performance of broilers

Group Add compound Average daily gain (g) Average meat ratio Survival rate (%) 1 - 41.3 2.168 100 2 Chlorobenzoquinone DL-lactate 48.4 2.045 100 3 Chlorobenzoquinone mesylate 42.2 2.119 100 4 Chlorobenzoquinone 2-hydroxyethyl sulfonate 49.1 2.019 100 5 Chlorobenzoquinone citrate 42.3 2.149 100 6 Chlorobenzoquinone tartrate 41.8 2.176 100 7 Chlorobenzoquinone benzoate 41.5 2.156 100 8 Chlorobenzoquinone succinate 41.7 2.144 100 9 Chlorobenzoquinone fumarate 42.6 2.151 100 10 Chlorobenzoquinone maleate 41.9 2.163 98.75 11 Chlorobenzoquinone acetate 41.1 2.176 100 12 Chlorobenzoquinone sulfate 42.0 2.146 100 13 Chlorobenzoquinone phosphate 42.4 2.126 100 14 Chlorobenzoic acid oxalate 41.8 2.154 97.5 15 Chloroquinone hydrochloride 45.2 2.073 100

Example 15: Effect of different doses of chlorophenyl hydrazine on performance of broilers

700 1 day old fast yellow broilers were divided into 7 groups according to 100/group. Different doses of chlorpheniramine DL-lactate were added to the same basal diet. Free feeding and drinking, continuous feeding during the experiment. For 30 days, the production performance and survival rate were counted (this test was carried out in cocci-sterilized cages to ensure no coccidiosis infection). The production performance test results are shown in Table 3. From the test results, different doses of chlorpheniramine DL-lactate have significantly improved the performance of broiler chickens, and the dosage performance is improved. The higher the dose, the more obvious the effect. Moreover, high doses have no negative impact on production performance.

Table 3 Test results of effects of different doses of chlorpheniramine DL-lactate on performance of broilers

*: The test dose is based on the dose of chlorophenyl hydrazine.

Example 16: Application effect of series of chlorpheniramine salts in pig feed

120 pairs of 65-day-old Du Dachang ternary heterozygous piglets with similar body weight were randomly divided into 6 groups, 20 in each group. A series of different types of chlorpheniramine salts were added to each group according to Table 4. The test period was free to eat and drink, and the test period was 28 days. The results showed that different types of chlorpheniramine series salt can increase the weight gain of the test pigs compared with the control group, and the feed ratio is improved to some extent, but chlorpheniramine DL-lactate and 2-hydroxyethylsulfonic acid The salt effect is better than the hydrochloride, followed by the mesylate and citrate. The test grouping and results are shown in Table 4.

Table 4 Grouping design and test results of the effects of different chlorpheniramine series salts on performance of pigs

Group Number of trials Add substance Dose *ppm Average daily gain (g) Ratio 1 20 - - 484 1.796 2 20 Chlorobenzoquinone DL-lactate 100 546 1.623 3 20 Chlorobenzoquinone mesylate 100 496 1.787

4 20 Chlorobenzoquinone 2-hydroxyethyl sulfonate 500 539 1.625 5 20 Chlorobenzoquinone citrate 100 485 1.801 6 20 Chloroquinone hydrochloride 1000 515 1.684

*: The dose is based on the content of chlorpheniramine.

Example 17 Application Effect of Chlorophenylhydrazine Series Salt in Duck Material

600 one-day-old cherry valley meat ducks were randomly divided into 6 groups of 100 animals each. Different types of chlorpheniramine series salts were added to each group according to Table 5. The test period was free to eat and drink, and the test period was 28 days. The results showed that different kinds of chlorpheniramine salts could increase the weight gain of the test ducks compared with the control group, and the feed ratio was improved to some extent. Among them, the lactate and 2-hydroxyethylsulfonate effects of chlorpheniramine Optimal and superior to the effect of hydrochloride, followed by oxalate and tartrate. The test grouping and results are shown in Table 5.

Table 5 Grouping design and test results of different chlorophenyl hydrazine salts on the performance of meat duck production

Group Number of trials Add substance Dose *ppm Average daily gain (g) Ratio 1 100 - - 58.2 1.987 2 100 Chlorobenzoquinone DL-lactate 50 68.4 1.845 3 100 Chlorobenzoic acid oxalate 50 61.2 1.965 4 100 Chlorobenzoquinone 2-hydroxyethyl sulfonate 50 67.9 1.851 5 100 Chlorobenzoquinone tartrate 50 60.8 1.959 6 100 Chloroquinone hydrochloride 50 64,2 1.926

*: The dose is based on the content of chlorpheniramine.

Claims (5)

A series of salts of chlorpheniramine whose structural formula is as shown in formula (1):

Wherein: R is DL-lactic acid, methanesulfonic acid, 2-hydroxyethylsulfonic acid, citric acid, tartaric acid, benzoic acid, succinic acid, fumaric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid or oxalic acid. Use of the series of salts of chlorinated benzoquinones according to claim 1 for the preparation of animal feed growth promoters. The use according to claim 2, characterized in that the animal is a farm animal of various growth stages. The use according to claim 3, characterized in that the farmed animal is a duck, a pig or a chicken. The use according to Claim 2, characterized in that the series of salts of chlorophenylhydrazine have an additive amount in the animal feed of from 0.1 to 1000 ppm.