CN111233831A - Dichroa febrifuga succinic acid monoester and preparation method and application thereof - Google Patents
Dichroa febrifuga succinic acid monoester and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a dichroa febrifuga succinic acid monoester, a preparation method and application thereof. The dichroa febrifuga ketone and succinic anhydride are grafted and modified to synthesize dichroa febrifuga copper succinate monoester for treating chicken coccidiosis, and the dichroa febrifuga succinate is good in water solubility, small in dosage, simple in preparation method, high in yield and high in purity.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to dichroa febrifuga copper succinate monoester and a preparation method and application thereof.
Background
Coccidiosis in chickens is a protozoal disease caused by one or more coccidia in the genus eimeria parasitizing in chicken intestinal epithelial cells. The disease has great harm to the chicken industry, the disease incidence rate reaches 80-100%, the disease death rate reaches 20-30%, the disease death rate reaches 80% in severe cases, the growth and development of diseased chicken flocks are retarded, and the worldwide loss due to coccidiosis reaches 30 hundred million. Generally, the feed intake of poultry and livestock infected with coccidiosis is decreased and the absorption rate of nutrients in the feed in the intestinal tract is also decreased, resulting in slow growth of poultry and livestock and easily inducing other diseases. At present, coccidiosis is mainly prevented and treated by feeding medicines.
The halofuginone has good anticoccidial effect, extremely low drug resistance, safety and low toxicity, so the halofuginone is an ideal anticoccidial drug. However, halofuginone tends to inhibit the synthesis of collagen in the skin, and if halofuginone is taken for a long time, the strength of the skin of broilers is reduced, and the skin may be damaged during the processing of finished products. In addition, the dichroa febrifuga is insoluble in water and has low biological activity. The dichromate is generally applied to clinic in the market. However, the synthesis yield of the halofuginone hydrobromide is low, the cost is high, and the water solubility is also to be improved.
However, the long-term use of the halofuginone hydrobromide causes serious coccidium drug resistance in most of the chicken farms at present, and the halofuginone hydrobromide has certain toxicity and is forbidden to young chickens or laying hens at a low week age. Therefore, the development of new-variety medicaments for treating the chicken coccidiosis is very important.
Disclosure of Invention
In view of the above, the invention aims to provide dichroa febrifuga copper succinate monoester with large synthesis amount, no toxicity and good coccidiosis resistance curative effect aiming at the defects of the prior art; also provides a preparation method for preparing the dichroa febrifuga copper succinate monoester, and the preparation method is simple and has high yield; simultaneously, also provides the application of the dichroa febrifuga succinic acid monoester for treating chicken coccidiosis.
In order to achieve the purpose, the invention adopts the following technical scheme:
a halofuginone succinic acid monoester salt has a structural formula as follows:
wherein M is any one of Na, K, meglumine, arginine or lysine.
A preparation method of halofuginone succinate monoester comprises the following steps:
a. dissolving halofuginone in an organic solution, and stirring at 30-80 ℃ to form a homogeneous phase to obtain a halofuginone solution; the organic solution is a mixed solution of an organic solvent I and water, wherein the organic solvent I accounts for 50-100% of the total mass of the mixed solution;
b. b, uniformly mixing succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a, refluxing and stirring for 1-5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga succinic acid monoester solid;
c. and c, placing the obtained halofuginone succinate solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinate monoester, adding corresponding alkali into the halofuginone succinate monoester, stirring, and cooling to obtain the halofuginone succinate monoester.
Preferably, the organic solvent I in step a refers to any one of ethanol, acetone, ethylene glycol, acetonitrile, propylene glycol, glycerol, tetrahydrofuran or 1, 4-dioxane.
Preferably, the molar ratio of the succinic anhydride to the catalyst in the step b is 1: 0.1-1.5.
Preferably, the catalyst is one or two of Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), triethylamine and pyridine, wherein the mass ratio of the two catalysts is 0-1: 1.
Preferably, the weight ratio of the added amount of the succinic anhydride to the halofuginone is 1: 1.2 to 5.0.
Preferably, in the step c, the organic solvent II is any one or two of ethanol, isopropanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, tetrahydrofuran and acetone, wherein the mass ratio of the two organic solvents II is 0-1: 1.
Preferably, the weight ratio of the halofuginone succinic acid monoester to the corresponding alkali in the step c is 1: 1.0-2.0.
Preferably, the corresponding base in step c is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, arginine, lysine or meglumine.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
The chemical mode in the reaction process of the invention is as follows:
the invention has the beneficial effects that:
the method achieves the modification effect on the functional group of the dichroa febrifuga by reacting the dichroa febrifuga with the succinic anhydride, changes the defect that the dichroa febrifuga is insoluble in water, improves the activity of the dichroa febrifuga, and enhances the effect of treating the coccidiosis of the chicken; the dichroa febrifuga succinic acid monoester salt is nontoxic, can be used for laying hens and young chickens, and does not inhibit the healthy growth of the chickens.
The preparation method is simple, easy to operate, high in product purity and large in output value.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A halofuginone succinic acid monoester sodium salt has a structural formula as follows:
wherein M is Na.
The preparation method of the halofuginone succinic acid monoester sodium salt comprises the following steps:
a. dissolving 1mol of halofuginone in a 50% ethanol solution, and stirring the mixture into a homogeneous phase at 80 ℃ to obtain a halofuginone solution;
b. b, uniformly mixing 5mol of succinic anhydride and 1.2mol of dicyclohexylcarbodiimide DCC, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid;
c. and c, placing the obtained halofuginone succinate monoester solid in the step b into ethanol for refluxing and dissolving to obtain halofuginone succinate monoester, adding 1mol of sodium hydroxide into the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate monoester sodium salt.
The obtained halofuginone succinic acid monoester sodium salt is white powder, and the yield is 76.52%. The purity of the product is 97.2 percent by HPLC (high performance liquid chromatograph); the molecular weight of the product is 537.5 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of the molecular weight of the target product of 537.75.
The preparation method is simple, easy to operate, high in product purity and large in output value.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 2
A preparation method of halofuginone succinic acid monoester sodium salt comprises the following steps:
a. dissolving 1mol of halofuginone in 80% acetone solution, and stirring at 60 ℃ to form homogeneous phase to obtain halofuginone solution;
b. uniformly mixing 1.2mol of succinic anhydride and 2mol of 4-dimethylaminopyridine DMAP, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 1 hour, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga succinic acid monoester solid;
c. and c, placing the obtained halofuginone succinate solid in the step b into acetonitrile to reflux and dissolve the halofuginone succinate solid into halofuginone succinate monoester, adding 2mol of sodium hydroxide into the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate monoester sodium salt.
The obtained halofuginone succinic acid monoester sodium salt is white powder, and the yield is 74.12%. The purity of the product was 94.28% by HPLC; the molecular weight of the product is 537.5 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of the molecular weight of the target product of 537.75.
The yield of halofuginone succinic acid monoester sodium salt prepared in this example was higher than that of example 1, but the purity of the product was relatively slightly lower.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 3
A preparation method of halofuginone succinic acid monoester sodium salt comprises the following steps:
a. dissolving 1mol of halofuginone in 80% acetonitrile aqueous solution, and stirring at 70 ℃ to form a homogeneous phase to obtain a halofuginone solution;
b. b, uniformly mixing 2.5mol of succinic anhydride and 0.5mol of pyridine, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 3 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid;
c. and c, placing the obtained halofuginone succinate solid in the step b into 1, 4-dioxane for refluxing and dissolving to obtain halofuginone succinate monoester, adding 1.5mol of sodium hydroxide into the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate monoester sodium salt.
The obtained halofuginone succinic acid monoester sodium salt is white powder, and the yield is 75.3%. The purity of the product was 93.6% by HPLC; the molecular weight of the product is 537.5 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of the molecular weight of the target product of 537.75.
The halofuginone succinic acid monoester sodium salt prepared in this example was relatively slightly lower in yield and purity than in example 1.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 4
A potassium dichroa succinate has the following structural formula:
wherein M is K.
The preparation method of the potassium dichroa febrifuga ketone succinate monoester comprises the following steps:
a. dissolving 1mol of halofuginone in 60% glycol solution, and stirring at 45 ℃ to form homogeneous phase to obtain halofuginone solution;
b. uniformly mixing 3mol of succinic anhydride and 4mol of triethylamine, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 5 hours, then acidifying by hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid;
c. and c, placing the obtained halofuginone succinate solid in the step b into N, N-dimethylformamide for refluxing and dissolving to obtain halofuginone succinate monoester, adding 1.5mol of potassium hydroxide into the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate potassium salt.
The obtained potassium dichromate succinate is white powder, and the yield is 75.2%. The purity of the product was 97.62% by HPLC; the molecular weight of the product is 553.9 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 553.86 of the molecular weight of the target product.
The potassium halofuginone succinate salt prepared in this example was more pure than the potassium halofuginone succinate salts prepared in examples 1-3.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 5
A preparation method of potassium dichromate succinate comprises the following steps:
a. dissolving 1mol of halofuginone in a 60% propylene glycol aqueous solution, and stirring the mixture into a homogeneous phase at 80 ℃ to obtain a halofuginone solution;
b. uniformly mixing 3mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 4 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga succinic acid monoester solid; wherein the catalyst is a mixture of 0.5mol of dicyclohexylcarbodiimide and 0.5mol of 4-dimethylaminopyridine;
c. and c, placing the obtained halofuginone succinate solid in the step b into tetrahydrofuran, refluxing and dissolving to obtain halofuginone succinate monoester, adding 1.5mol of potassium carbonate to the halofuginone succinate monoester in batches, stirring, and cooling to obtain halofuginone succinate monoester potassium salt.
The obtained potassium dichromate succinate is white powder, and the yield is 71.8%. The purity of the product is 94.5% by HPLC; the molecular weight of the product is 553.9 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 553.86 of the molecular weight of the target product.
The potassium halofuginone succinate salt prepared in this example was relatively low in both yield and purity compared to example 4.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 6
A dichroa succinic acid monoester arginine salt has a structural formula as follows:
wherein M is arginine.
The preparation method of the dichroa febrifuga succinic acid monoester arginine salt comprises the following steps:
a. dissolving 1mol of halofuginone in a 50% glycerol aqueous solution, and stirring the mixture into a homogeneous phase at 50 ℃ to obtain a halofuginone solution;
b. b, uniformly mixing 2mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid; wherein the catalyst is a mixture of 0.2mol of triethylamine and 0.3mol of pyridine;
c. and c, placing the solid of the halofuginone succinate obtained in the step b into a mixed solvent of 1mol of ethanol and acetonitrile which are mixed in equal proportion, refluxing and dissolving the solid into the halofuginone succinate, adding 1.5mol of arginine into the halofuginone succinate in batches, stirring, and cooling to obtain the halofuginone succinate arginine salt.
The obtained halofuginone succinic acid monoester arginine salt is white powder, and the yield is 79.5%. The purity of the product is 96.25% by HPLC; the molecular weight of the product is 688.7 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 688.96 of the molecular weight of the target product.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 7
A preparation method of dichroa febrifuga succinic acid monoester arginine salt comprises the following steps:
a. dissolving 1mol of halofuginone in 75% ethanol water solution, and stirring at 50 ℃ to form a homogeneous phase to obtain a halofuginone solution;
b. b, uniformly mixing 4mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, then refluxing and stirring for 2.5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid; wherein the catalyst is a mixture of 0.6mol of 4-dimethylaminopyridine DMAP, 0.1mol of triethylamine and 0.9mol of pyridine;
c. and c, placing the solid halofuginone succinate obtained in the step b into a mixed solvent of 1mol of N, N-dimethylformamide and N, N-dimethylacetamide which are mixed in equal proportion, refluxing and dissolving to obtain the halofuginone succinate, adding 1.5mol of arginine into the halofuginone succinate in batches, stirring, and cooling to obtain the halofuginone succinate arginine salt.
The obtained halofuginone succinic acid monoester arginine salt is white powder, and the yield is 81%. The purity of the product was 97.47% by HPLC; the molecular weight of the product is 688.9 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 688.96 of the molecular weight of the target product.
The yield and purity of the halofuginone succinate monoester arginine salt prepared in this example were higher than those of example 7.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 8
A dichroa succinic acid monoester lysine salt has the following structural formula:
wherein M is lysine.
The preparation method of the dichroa febrifuga succinic acid monoester lysine salt comprises the following steps:
a. dissolving 1mol of halofuginone in 70% tetrahydrofuran aqueous solution, and stirring at 80 ℃ to form a homogeneous phase to obtain a halofuginone solution;
b. uniformly mixing 3.5mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, then refluxing and stirring for 4.5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid; wherein the catalyst is a mixture of 0.2mol of triethylamine and 0.3mol of dicyclohexylcarbodiimide DCC;
c. and c, placing the obtained halofuginone succinic acid monoester solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinic acid monoester, adding 1.5mol of lysine into the halofuginone succinic acid monoester in batches, stirring, and cooling to obtain the halofuginone succinic acid monoester lysine salt.
The obtained halofuginone succinic acid monoester lysine salt is white powder, and the yield is 86.1%. The purity of the product was 98.14% by HPLC; the molecular weight of the product is 660.7 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 660.95 of the molecular weight of the target product.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 9
A dichroa leaf succinic acid monoester meglumine salt has a structural formula as follows:
wherein M is meglumine.
The preparation method of the dichroa febrifuga succinic acid monoester meglumine salt comprises the following steps:
a. dissolving 1mol of halofuginone in 70% 1, 4-dioxane aqueous solution, and stirring at 60 ℃ to form homogeneous phase to obtain halofuginone solution;
b. b, uniformly mixing 2mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid; wherein the catalyst is a mixture of 0.1mol of dicyclohexylcarbodiimide DCC, 0.1mol of 4-dimethylaminopyridine DMAP and 0.1mol of pyridine;
c. and c, placing the obtained halofuginone succinate solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinate monoester, adding 2mol of meglumine to the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate meglumine salt, wherein the organic solvent II is a mixed solvent of 1mol of acetonitrile and 0.5mol of acetone.
The prepared halofuginone succinate monoester meglumine salt is white powder, and the yield is 87.2%. The purity of the product was 97.56% by HPLC; the molecular weight of the product is 709.7 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 709.98 of the molecular weight of the target product.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 10
A preparation method of halofuginone succinate monoester meglumine salt comprises the following steps:
a. dissolving 1mol of halofuginone in 90% acetonitrile aqueous solution, and stirring the mixture into a homogeneous phase at the temperature of 80 ℃ to obtain a halofuginone solution;
b. b, uniformly mixing 3mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, then refluxing and stirring for 3 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga monoester solid; wherein the catalyst is a mixture of 0.1mol of dicyclohexylcarbodiimide DCC, 0.2mol of 4-dimethylaminopyridine DMAP and 0.3mol of pyridine;
c. and c, placing the obtained halofuginone succinate monoester solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinate monoester, adding 1.5mol of meglumine to the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate meglumine salt, wherein the organic solvent II is a mixed solvent of 1mol of acetonitrile and 1mol of 1, 4-dioxane.
The prepared halofuginone succinate monoester meglumine salt is white powder, and the yield is 89.8%. The purity of the product was 97.58% by HPLC; the molecular weight of the product is 709.7 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 709.98 of the molecular weight of the target product.
The yield and purity of halofuginone succinate monomethylether meglumine salt prepared in this example were higher than those of example 9.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in animal in-vivo disinsection.
Example 11
A preparation method of halofuginone succinate monoester meglumine salt comprises the following steps:
a. dissolving 1mol of halofuginone in 85% tetrahydrofuran aqueous solution, and stirring at 65 ℃ to form a homogeneous phase to obtain a halofuginone solution;
b. uniformly mixing 3mol of succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a in batches, refluxing and stirring for 4 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga succinic acid monoester solid; wherein the catalyst is a mixture of 0.3mol of dicyclohexylcarbodiimide DCC, 0.2mol of 4-dimethylaminopyridine DMAP and 0.1mol of triethylamine;
c. placing the obtained halofuginone succinate solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinate monoester, adding 1.5mol of meglumine to the halofuginone succinate monoester in batches, stirring, and cooling to obtain the halofuginone succinate meglumine salt, wherein the organic solvent II is a mixed solvent of 0.5mol of tetrahydrofuran and 1mol of 1, 4-dioxane.
The prepared halofuginone succinate monoester meglumine salt is white powder, and the yield is 85.4%. The purity of the product is 98.34% by HPLC; the molecular weight of the product is 709.9 determined by FAB-MS (fast atom bombardment mass spectrometry), which is consistent with the theoretical calculated value of 709.98 of the molecular weight of the target product.
The yield of halofuginone succinate monomethylether meglumine salt prepared in this example was slightly lower than that of example 10, but the purity of the product was higher.
The invention also provides application of the dichroa febrifuga succinic acid monoester salt in killing pests in animals.
HPLC (high performance liquid chromatograph) comprises an Shimadzu SCL-6A controller, an SPD-6AV ultraviolet detector and an Shimadzu C-R3A processor; the chromatographic column is Kromasil C18 column, 250mm × 4.6mm, 5 μm; mobile phase: acetonitrile-acetate buffer (0.25mol/L ammonium acetate, pH adjusted to 4.3 with acetic acid) -water in a ratio of 5: 3: 12 (V/V/V); the flow rate is 2.0 mL/min; the detection wavelength is 243 nm; the sample volume is 20 mu L; the column temperature is (23 +/-3) DEG C.
Electrospray mass spectrometer, Amazon SL, Bruker, Switzerland, FAB-MS (fast atom bombardment Mass Spectrometry).
And (3) analyzing the comparative experiment result:
the reference product of the halofuginone hydrobromide is provided by the Chinese veterinary medicine supervision with the purity of more than or equal to 98%.
1 solubility comparison
Respectively weighing 0.1g of the prepared dichroa febrifuga succinic acid monoester salt and dichroa febrifuga copper and a certain amount of distilled water at 25 ℃, shaking vigorously for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes until no visible solute particles exist, namely completely dissolving, recording the volume of the distilled water corresponding to 0.1g of powder, and comparing the test result with the explanation corresponding to the solubility noun terms in pharmacopoeia to obtain the corresponding substance solubility determination result, wherein the test result is shown in table 1:
| test object | Volume of distilled Water (ml) | Solubility in water |
| Halofuginone | >1000 | Minimal dissolution |
| Halofuginone hydrobromide | 48.95 | Slightly soluble |
| Halofuginone succinic acid monoester sodium salt | 40.15 | Slightly soluble |
| Potassium dichromate succinate | 37.25 | Slightly soluble |
| Dichrone succinic acid monoester meglumine salt | 32.87 | Slightly soluble |
| Dichrone succinic acid monoester arginine salt | 35.27 | Slightly soluble |
| Dichrone succinic acid monoester lysine salt | 38.18 | Slightly soluble |
As can be seen from Table 1, the water solubility of the dichroa febrifuga copper succinate monoester salt prepared by the invention is better than that of the dichroa febrifuga ketone.
The halofuginone is a very slightly soluble substance, the solubility in water is poor, the concentration of drinking water is too low due to uneven dispersion of the medicine in the drinking water generally, but the halofuginone succinic acid monoester salt in the embodiment is similar to the halofuginone hydrobromide in actual clinic, the solubility is good, and the dosage is low.
2 comparison of results for pharmaceutical applications
(1) Test samples:
each 50g of premix contains 0.3g of the example drug, and a control group selects halofuginone hydrobromide with the same specification, which is provided by poultry scientific research institute of Jiangsu province of oocyst system used for artificial infection.
(2) Chicken infection test
70 healthy 15-day-old chicks were selected in a certain farm in Guangzhou Huadu, and were divided into 7 groups for a total test period of 8 days. The control group was not infected and not dosed, and the test group was dosed with 500mg/kg of halofuginone hydrobromide premix and 500mg/kg of the example drug after infection.
The components are fed in cages, a control group is fed with drug-free feed, each test group is inoculated with 12 ten thousand of Eimeria tenella embranelized oocysts through mouth when each chicken is 15 days old, the corresponding drug-mixed feed is fed immediately after inoculation, the number of piles of blood dung of each group is recorded every day, the average number of piles of the blood dung discharged by each chicken on the day is calculated, and the blood dung is convenient to be deducted according to the day with the most serious blood dung. Immediately weighing the chickens which die in the midway of the test, recording the wing numbers, performing a cesarean examination and a cecal mucosa scraping object microscopic examination, judging the death reasons, inoculating oocysts on the 8 th day to kill the surviving chickens, scoring lesions, counting oocysts in cecal homogenate, and counting the oocysts in feces of the 6 th, 7 th and 8 th days after inoculation if the chickens die of non-coccidiosis and are not counted.
(3) Results of the experiment
The results of the infection test groups are shown in Table 2.
Table 2 infection test results of each group
| Survival rate | Rate of change of disease | Deduction of blood dung | Oocyst number 106 | |
| Control group (no infection, no administration) | 100％(10/10) | 0 | 0 | 0 |
| Halofuginone hydrobromide | 100％(10/10) | 10％ | 0 | 0 |
| Halofuginone succinic acid monoester sodium salt | 100％(10/10) | 10％ | 0 | 0 |
| Potassium dichromate succinate | 100％(10/10) | 10％ | 0 | 0 |
| Dichrone succinic acid monoester meglumine salt | 100％(10/10) | 10％ | 0 | 0 |
| Dichrone succinic acid monoester arginine salt | 100％(10/10) | 10％ | 0 | 0 |
| Dichrone succinic acid monoester lysine salt | 100％(10/10) | 10％ | 0 | 0 |
As can be seen from Table 2, the survival rate of the control group was 100%, no lesions, blood droppings and oocysts, indicating that the test chickens were not infected with coccidia during the test. In the test groups, neither the halofuginone hydrobromide group nor the halofuginone succinate monoester salt group in the examples had blood dung and oocysts, and the disease rate was 10%, which indicates that the halofuginone succinate monoester salt group in the examples is equivalent to the halofuginone hydrobromide group, and has a better effect of treating coccidium infection.
The experimental results show that the halofuginone succinate monoester prepared by the method has better solubility, can be dissolved in normal drinking water of chickens, has good curative effect on chicken coccidiosis, small dosage, small toxicity and small influence on the growth of young chickens.
Finally, the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting, and other modifications or equivalent substitutions made by the technical solutions of the present invention by those of ordinary skill in the art should be covered within the scope of the claims of the present invention as long as they do not depart from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The dichroa febrifuga ketone succinic acid monoester salt is characterized by having the following structural formula:
wherein M is any one of Na, K, meglumine, arginine or lysine.
2. A process for the preparation of halofuginone succinate monoester salt according to claim 1, characterized by comprising the steps of:
a. dissolving halofuginone in an organic solution, and stirring at 30-80 ℃ to form a homogeneous phase to obtain a halofuginone solution; the organic solution is a mixed solution of an organic solvent I and water, wherein the organic solvent I accounts for 50-100% of the total mass of the mixed solution;
b. b, uniformly mixing succinic anhydride and a catalyst, adding the mixture into the dichroa febrifuga copper solution obtained in the step a, refluxing and stirring for 1-5 hours, then acidifying with hydrochloric acid until the pH value is 6, and naturally cooling to room temperature to obtain a dichroa febrifuga succinic acid monoester solid;
c. and c, placing the obtained halofuginone succinate solid in the step b into an organic solvent II for refluxing and dissolving to obtain halofuginone succinate monoester, adding corresponding alkali into the halofuginone succinate monoester, stirring, and cooling to obtain the halofuginone succinate monoester.
3. The process for producing the halofuginone succinic monoester salt according to claim 2, wherein the organic solvent i in the step a is any one of ethanol, acetone, ethylene glycol, acetonitrile, propylene glycol, glycerol, tetrahydrofuran and 1, 4-dioxane.
4. The method for preparing the halofuginone succinic acid monoester salt according to claim 2, wherein the molar ratio of the succinic anhydride to the catalyst in the step b is 1: 0.1-1.5.
5. The method for preparing the halofuginone succinic monoester salt according to claim 2 or 4, wherein the catalyst is one or two of Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), triethylamine and pyridine, and the mass ratio of the two catalysts is 0-1: 1.
6. The process for producing a halofuginone succinic acid monoester salt according to claim 2, wherein the weight ratio of the added amount of the succinic anhydride to the halofuginone is 1: 1.2 to 5.0.
7. The method for preparing the halofuginone succinic acid monoester salt according to claim 2, wherein the organic solvent II in the step c is any one or two of ethanol, isopropanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, tetrahydrofuran and acetone, and the mass ratio of the two organic solvents II is 0-1: 1.
8. The method for preparing the halofuginone succinic acid monoester salt according to claim 2, wherein the weight ratio of the halofuginone succinic acid monoester to the corresponding base in the step c is 1: 1.0-2.0.
9. The method for preparing the halofuginone succinate monoester salt according to claim 2, wherein the corresponding base in the step c is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, arginine, lysine or meglumine.
10. Use of the halofuginone succinate monoester salt according to claim 1 or the halofuginone succinate monoester salt prepared by the method according to any one of claims 2-9 for disinsection in animals.
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| JP2002201192A (en) * | 2000-12-28 | 2002-07-16 | Japan Science & Technology Corp | New method for synthesizing febrifugine and febrifugine compound |
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