CN110981855B

CN110981855B - Purification method of high-residue amproline hydrochloride

Info

Publication number: CN110981855B
Application number: CN201911248228.1A
Authority: CN
Inventors: 王国平; 徐旭辉; 李刚; 赵东升
Original assignee: ZHEJIANG DAYANG BIOTECH GROUP CO Ltd
Current assignee: ZHEJIANG DAYANG BIOTECH GROUP CO Ltd
Priority date: 2019-12-09
Filing date: 2019-12-09
Publication date: 2020-10-30
Anticipated expiration: 2039-12-09
Also published as: CN110981855A

Abstract

The invention discloses a method for purifying high-residue amproline hydrochloride, which comprises the following steps: dissolving high-residue amprolium hydrochloride in methanol at a reflux temperature or amprolium hydrochloride methanol mother liquor I obtained in the subsequent step, and filtering while hot to respectively obtain an amprolium hydrochloride methanol solution II after impurity removal and solid residue; cooling and crystallizing the amproline hydrochloride methanol solution II after impurity removal to obtain amproline hydrochloride slurry after cooling and crystallization; centrifugally drying the slurry to respectively obtain an amprolium hydrochloride wet product I and an amprolium hydrochloride methanol mother liquor I; adding isopropanol into the wet product I for pulping, and then centrifugally drying to obtain an amproline hydrochloride wet product II and an amproline hydrochloride isopropanol mother liquor I; and drying and crushing the wet product II to obtain the amproline hydrochloride. The purification method has the advantages of high product yield, high quality and simple process, and the used solvent can be recycled.

Description

Purification method of high-residue amproline hydrochloride

Technical Field

The invention belongs to the field of chemical medicines, relates to a preparation technology of veterinary drug bulk drugs, and particularly relates to a purification method of high-residue amproline hydrochloride.

Background

Aminoproline hydrochloride, also known as Amproponium hydrochloride, was first developed in the 60's last century by Rogers of Merck corporation. It is easy to dissolve in water, stable in property, no change when stored at room temperature and below 40 deg.c for 5 years, and has the advantages of low toxicity, wide safety range, less residue, no need of stopping medicine period, etc. In recent years, serious drug resistance is generated to a plurality of medicines by coccidiosis, so that a plurality of cases of failure in prevention and treatment are caused, and due to the unique action mechanism of the amprolium hydrochloride, the coccidium growth is inhibited by competitively inhibiting the ingestion of thiamine by the coccidium, so that the coccidium hydrochloride is widely applied to various countries in the world at present, and the annual demand of the coccidium is more than 1000 tons.

During the production process of the aminoproline hydrochloride, the intermediate obtained in the cyclization procedure is extracted from sodium chloride and sodium hydroxide solution through an organic solvent, and during the operation process, the sodium chloride and the sodium hydroxide solution are difficult to be ensured not to be mixed into an organic phase, so that the residue in the final finished product is higher.

Although the use effect of the amproline hydrochloride is not influenced by the sodium chloride, the current European standard control is very strict, the residue is required to be less than 0.1 percent, and the Chinese veterinary pharmacopoeia stipulates that the residue is less than 0.5 percent, so the conventional production process is difficult to achieve. Production enterprises have to adopt refining means for purification, such as adopting water or organic solvent for dissolving and recrystallization, but the residue of the refined aminoproline hydrochloride mother liquor is higher, no good means is available for re-purification, and the residue can only be treated as solid waste, so that the yield of the final product is low, the production cost is high, and three-waste pollution is caused.

In an attempt to solve the technical problems existing in the prior art, the inventors have conducted the following experiments in the course of the invention:

the inventor tries to dissolve high-residue amprolium hydrochloride into methanol under the condition of heating by using the methanol as a solvent, add activated carbon for decolorization, carry out reduced pressure distillation and concentration, cool and centrifugally spin-dry to obtain an amprolium hydrochloride wet product, and obtain a finished product after bipyramid or airflow drying. After methanol dissolution and active carbon decoloration and refining, the main content of the obtained amproline hydrochloride and related impurities can meet the requirements, but the ignition residues still far exceed the standard requirements, and the problem that the solvent residues of methyl chloride and dimethyl ether exceed the standard is generated. The inventor finds that in a hydrogen chloride system, methyl chloride is generated by the reaction of methanol and hydrogen chloride at high temperature, and dimethyl ether is generated by the condensation of the methanol, so that the problem that the residue of the aminoproline hydrochloride solvent exceeds the standard is caused. Also, a large amount of residue and a mother liquor feed with higher impurities are produced.

The inventor also tries to dissolve the high residue amprolium hydrochloride into water by using water as a solvent under the heating condition, adding activated carbon for decolorization, carrying out reduced pressure distillation and concentration, cooling and centrifuging for spin-drying to obtain an amprolium hydrochloride wet product, and drying by a double cone or air flow to obtain a finished product. After water dissolution and active carbon decoloration and refining, the main content of the obtained amproline hydrochloride and related impurities can meet the requirements, the problem of solvent residue is solved, but the burning residue still far exceeds the standard requirement. Meanwhile, the crystallization conditions of the amproline hydrochloride in water and an organic solvent are different, the crystal forms are also different, the solubility of the crystal amorphous particles in water is poor, and the crystal obtained by crystallization in the solvent is needle-shaped, so the solubility of the crystals is greatly different. Although the prior literature does not indicate which form is better, for practical use, the customer prefers to use the crystalline form of amproline hydrochloride in a solvent. Also, a large amount of residue and a mother liquor material with higher impurities are produced.

The present inventors further refer to the method of the invention of Wang Guo et al, method for preparing highly pure granular form of amproline hydrochloride (201510770969.1), wherein the high residue (ignition residue 10.02%) of amproline hydrochloride is purified, and the ignition residue of the obtained purified amproline hydrochloride is 9.16%, which far exceeds the requirement of quality standard (less than 0.5%).

In view of the above, there is a need for improvements in the prior art.

Disclosure of Invention

The invention aims to provide a method for purifying high-residue amproline hydrochloride. The purification method has the advantages of high product yield, high quality and simple process, and the used solvent can be recycled.

In order to solve the technical problem, the invention provides a method for purifying high-residue amproline hydrochloride, which comprises the following steps:

1) dissolving the high residue amproline hydrochloride in methanol at the reflux temperature or the amproline hydrochloride methanol mother liquor I obtained in the subsequent step 4), so that the amproline hydrochloride contained in the high residue amproline hydrochloride is completely dissolved (just completely dissolved) to obtain an amproline hydrochloride methanol solution I;

description of the drawings: in the step, the high residue of the amprolium hydrochloride is completely dissolved, but the sodium chloride is not dissolved, so that the impurity removal can be realized through the difference of concentration;

in the first production, methanol is used for dissolution; during subsequent production, the amproline hydrochloride methanol mother liquor I obtained in the step 4) can be adopted for dissolution;

2) filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (for example, a filter pressing removal method can be adopted), and respectively obtaining an alanine hydrochloride methanol solution II and solid residues after impurity removal;

3) transferring the amprolium hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle (immediately transferring into the crystallization kettle), and cooling (to 15-20 ℃) for crystallization to obtain amprolium hydrochloride slurry after cooling crystallization;

in the step, cooling water can be introduced for cooling crystallization under stirring;

4) centrifugally drying the amprolium hydrochloride slurry cooled and crystallized in the step 3) to respectively obtain an amprolium hydrochloride wet product I and an amprolium hydrochloride methanol mother liquor I;

5) putting the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) into a pulping kettle, adding isopropanol to carry out pulping (stirring and pulping time is 30-60 min), and then centrifugally drying to obtain a wet product II of the aminopropyl amine hydrochloride and a mother solution I of the aminopropyl amine isopropanol hydrochloride;

6) drying (drying) and crushing the wet product II of the aminopropyl amine hydrochloride obtained in the step 5) to obtain the aminopropyl amine hydrochloride (finished product of the aminopropyl amine hydrochloride).

As an improvement of the purification method of high residue amprolium hydrochloride, the method also comprises the following step 7):

distilling (vacuum distilling) the alanine isopropyl alcohol hydrochloride mother liquor I obtained in the step 5) to obtain an isopropanol crude product and a residual liquid, rectifying and dehydrating the isopropanol crude product (until the water content is less than 0.5 percent) to obtain the recovered isopropanol, and returning to the step 5) for recycling.

Namely, after the crude isopropanol is rectified and dehydrated, the obtained recovered isopropanol is refined isopropanol.

As a further improvement of the purification method of high residue amproline hydrochloride, alkali (liquid alkali) is added into the residual liquid obtained in the step 7), the pH value is adjusted to 10-10.5, and then 2-methylpyridine is distilled and recovered.

As a further improvement of the method for purifying high residue amproline hydrochloride of the present invention, in the step 1), in order to make the amproline hydrochloride just completely dissolved:

the weight ratio of the high residue amprolium hydrochloride to the methanol is 1: 2.5-4.5;

or the weight ratio of the high-residue amprolium hydrochloride to the amprolium hydrochloride methanol mother liquor I obtained in the step 4) is 1 (7 +/-0.5).

As a further improvement of the high residue amproline hydrochloride purification method of the invention,

the weight ratio of the amprolium hydrochloride wet product I to the isopropanol in the step 5) is 1: 0.5-1.

Description of the drawings: the dosage of the isopropanol can be adjusted according to the content of the 2-methylpyridine in the wet amprolium hydrochloride I.

The high residue amproline hydrochloride used in the invention is derived from waste residues generated by a recrystallization process of the existing amproline hydrochloride refining technology, and the high residue amproline hydrochloride has the following quality indexes:

the content of the aminopropionine hydrochloride (calculated by dry basis) is more than 50 percent; the ignition residue is more than 0.5 percent; the appearance is earthy yellow to grey brown; the above percentages are mass%.

Compared with the prior art, the invention has the following technical advantages:

the invention utilizes the solubility difference of methanol to the alanine hydrochloride and the sodium chloride, adopts a supersaturation filtration and cooling crystallization method to refine the alanine hydrochloride with high residue, then carries out pulping and washing by isopropanol to remove the methanol and other solvent residues, and each index of the obtained alanine hydrochloride is superior to the quality standard, and simultaneously, the residue is separated from the system in the form of sodium chloride solid, thereby improving the refining yield of the alanine hydrochloride and further reducing the production cost.

Drawings

The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.

FIG. 1 is a process flow diagram of the purification method of high residue amproline hydrochloride of the present invention.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.

The rotating speed of stirring and pulping is 100-300 r/min;

the centrifugal spin-drying is performed for 3-5 minutes at the rotating speed of 500-800 r/min.

All% of the following, which are not particularly specified, are mass%.

Example 1-1, a method of purifying high residue amproline hydrochloride, sequentially performing the following steps:

1) 500kg of highly residual aminopropyline hydrochloride was charged into a 3000L dissolution vessel, and 2250kg of methanol was further charged (i.e., the weight ratio of highly residual aminopropyline hydrochloride to methanol was 1: 4.5), closing a feed port, opening an inlet and outlet cooling circulating water valve of a reflux condenser, introducing steam into a jacket for heating, when the temperature in the kettle reaches 72 ℃, allowing liquid drops to be formed at an outlet of the condenser, starting methanol reflux, sampling and observing, and completely dissolving the amproline hydrochloride to obtain 2750kg of amproline hydrochloride methanol solution I.

The high residue amproline hydrochloride has the following quality indexes: the content of the amproline hydrochloride (calculated by dry basis) is 97.47 percent, the ignition residue is 0.53 percent, the 2-methylpyridine is 1.22 percent, and the rest is other impurities, and the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 2750kg of an alanine hydrochloride methanol solution II after impurity removal and less than 0.1kg of solid residues.

Note: since the amount of solid residue produced was very small and was negligible, the amount of solid residue was 2750kg in this case, based on the total weight of the amproline hydrochloride methanol solution i.

3) And 2) immediately (while the solution is hot) transferring 2750kg of the amprolium hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle, introducing cooling water while stirring for cooling, and cooling to 15-20 ℃ to obtain crystallized amprolium hydrochloride slurry.

4) And centrifugally drying the amproline hydrochloride slurry cooled and crystallized in the step 3) to obtain 310kg of amproline hydrochloride wet product I and 2440kg of amproline hydrochloride methanol mother liquor I.

5) And putting 310kg of the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding 155kg of isopropanol (namely, the weight ratio of the wet amprolium hydrochloride I to the isopropanol is 1:0.5), stirring and pulping for 30min, and then carrying out centrifugal drying to obtain 300kg of wet amprolium hydrochloride II and 165kg of mother liquor I of the amprolium hydrochloride isopropanol.

6) And drying (drying at 105 ℃ for about 3-5 hours) 300kg of the wet product II of the aminopropyl-amine hydrochloride obtained in the step 5), crushing (sieving by a 40-mesh sieve) and packaging to obtain 285kg of finished product of the aminopropyl-amine hydrochloride and warehousing.

The finished product of the amproline hydrochloride is detected to have the following quality indexes: 99.53 percent of amproline hydrochloride, 0.23 percent of ignition residue, 0.19 percent of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.12 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) And carrying out reduced pressure distillation on 165kg of the alanine hydrochloride isopropanol mother liquor I obtained in the step 5) (the pressure is-0.08 Mpa, the distillation temperature is not more than 110 ℃) to obtain 159kg of distilled isopropanol (crude isopropanol) and 6kg of residual liquid.

8) Adding liquid alkali (30% NaOH solution) into 6kg of residual liquid obtained in the step 7) to adjust the pH to 10.5, and distilling and recycling 4.3 kg of 2-methylpyridine. The bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of 2-methylpyridine is about 96.3%.

9) 159kg of isopropanol (crude isopropanol) obtained by distillation in the step 7) is dehydrated by rectification (rectification under normal pressure and collection of 68-72 ℃ fractions) and an inorganic vaporization permeable membrane (for example, an inorganic vaporization permeable membrane device provided by Jiangsu Jieshian Kogaku company can be selected) to obtain about 153 kg of refined isopropanol with the water content of less than 0.5%, and the refined isopropanol returns to the step 5) for recycling.

Description of the drawings: replacing the isopropanol originally used in the step 5) with the isopropanol recovered in the step 9), and keeping the volume amount unchanged; the results obtained were identical to those of example 1-1; i.e. no significant difference.

Example 1-2, the "methanol" in step 1) of example 1-1 was changed to "alanine hydrochloride methanol mother liquor i" obtained in step 4) of example 1-1, so that the weight ratio of alanine hydrochloride and alanine hydrochloride methanol mother liquor i was 1: 7.14; the rest is equivalent to the embodiment 1-1, and the specific steps are as follows:

1) putting 350kg of high-residue amprolium hydrochloride into a 3000L dissolving kettle, putting 2500kg of amprolium hydrochloride methanol mother liquor I obtained in the step 4) of the embodiment 1-1, closing a feeding port, opening an inlet/outlet cooling circulating water valve of a reflux condenser, introducing steam into a jacket for heating, when the temperature in the kettle reaches 72 ℃, liquid drops exist at an outlet of the condenser, methanol starts to flow back, sampling and observing, and completely dissolving the amprolium hydrochloride to obtain the amprolium hydrochloride methanol solution I.

The quality index of high residue amproline hydrochloride is the same as that of example 1-1.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 2847kg of an alanine hydrochloride methanol solution II after impurity removal and about 3kg of solid residues.

3) Transferring 2847kg of the amproline hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle immediately, introducing cooling water to cool the solution to 15-20 ℃ while stirring, and obtaining crystallized amproline hydrochloride slurry.

4) And centrifugally drying the amproline hydrochloride slurry cooled and crystallized in the step 3) to obtain 345kg of amproline hydrochloride wet product I and 2502kg of amproline hydrochloride methanol mother liquor I.

5) Putting 345kg of the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding 172.5kg of isopropanol (namely, the weight ratio of the wet amprolium hydrochloride I to the isopropanol is 1:0.5), stirring and pulping for 30min, and then carrying out centrifugal drying to obtain 335kg of wet amprolium hydrochloride II and 182.5kg of mother liquor I of the amprolium hydrochloride isopropanol.

6) Drying, crushing and packaging 335kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 318kg of finished product to be put in storage.

The quality indexes of the finished product of the amproline hydrochloride obtained in the embodiment are as follows through detection: 99.55 percent of amproline hydrochloride, 0.25 percent of ignition residue, 0.19 percent of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.12 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) Distilling 182.5kg of the alanine hydrochloride isopropanol mother liquor I obtained in the step 5) under reduced pressure to obtain 176.5kg of distilled isopropanol and 6kg of residual liquid.

8) Adding liquid alkali into the residual liquid obtained in the step 6) to adjust the pH value to 10.5, distilling and recycling 5.4 kg of 2-methylpyridine, wherein the bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain 168 kilograms of refined isopropanol with the water content of less than 0.5 percent, and returning to the step 5) for recycling.

Examples 1-3, the amount of isopropanol used in step 5) of examples 1-2 was changed from 172.5kg to 345kg (i.e., the weight ratio of amprolium hydrochloride wet product i to isopropanol was 1:1), and the remainder was the same as in examples 1-2, specifically as follows:

steps 1) to 4) are the same as steps 1) to 4) of examples 1 to 2.

5) Putting 345kg of the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding 345kg of isopropanol (namely, the weight ratio of the wet amprolium hydrochloride I to the isopropanol is 1:1), stirring and pulping for 30min, and then carrying out centrifugal drying to obtain 335kg of wet amprolium hydrochloride II and 355kg of mother liquor of the amprolium hydrochloride isopropanol I.

The quality indexes of the obtained amproline hydrochloride finished product are as follows through detection: 99.52 percent of amproline hydrochloride, 0.26 percent of ignition residue, 0.15 percent of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.11 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) 355kg of alanine hydrochloride isopropanol mother liquor I obtained in the step 5) is subjected to reduced pressure distillation to obtain 349kg of distilled isopropanol and 6kg of residual liquid.

8) Adding liquid alkali into 6kg of residual liquid obtained in the step 6) to adjust the pH value to 10.5, distilling and recycling 5.5 kg of 2-methylpyridine, wherein the bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain refined isopropanol (340 kg) with the water content of less than 0.5%, and returning to the step 5) for recycling.

Example 2, change the quality of the high residue amproline hydrochloride used in the step 1), namely, the ignition residue in the quality index of the high residue amproline hydrochloride is improved from 0.53 percent to 10.02 percent, and the rest is equal to the example 1-1, and the following steps are sequentially carried out:

1) 500kg of high-residue amprolium hydrochloride was put into a 3000L dissolution vessel, and 2250kg of methanol (i.e., the weight ratio of high-residue amprolium hydrochloride to methanol was 1: 4.5), closing a feed port, opening an inlet and outlet cooling circulating water valve of a reflux condenser, introducing steam into a jacket for heating, when the temperature in the kettle reaches 72 ℃, allowing liquid drops to be formed at an outlet of the condenser, starting methanol reflux, sampling and observing, and completely dissolving the amproline hydrochloride to obtain 2750kg of amproline hydrochloride methanol solution I.

The quality indexes of the high residue amproline hydrochloride are as follows: the content of the amproline hydrochloride (calculated by dry basis) is 87.31 percent, the ignition residue is 10.02 percent, the 2-methylpyridine is 1.67 percent, and the rest is other impurities, and the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 2725kg of an alanine hydrochloride methanol solution II after impurity removal and 25kg of solid residue.

3) 2725kg of the amproline hydrochloride methanol solution II obtained in the step 2) after impurity removal is immediately transferred into a crystallization kettle, and cooling water is introduced to cool the solution to 15-20 ℃ while stirring, so as to obtain crystallized amproline hydrochloride slurry.

4) And centrifugally drying the cooled and crystallized aminopropyl hydrochloride slurry obtained in the step 3) to obtain 247kg of aminopropyl hydrochloride wet product I and 2478kg of aminopropyl hydrochloride methanol mother liquor I.

5) Putting 247kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) into a pulping kettle, adding 247kg of isopropanol, stirring and pulping for 60min, and then carrying out centrifugal drying to obtain 245kg of wet product II of the aminopropyl amine hydrochloride and 249kg of mother liquor I of the aminopropyl amine hydrochloride isopropanol.

6) And drying, crushing and packaging 245kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 233kg of finished product to be stored.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 99.56 percent of aminoproline hydrochloride, 0.27 percent of residue, 0.14 percent of 2-methylpyridine and the balance of other impurities, the drying weight loss is 0.11 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) 249kg of alanine hydrochloride isopropanol mother liquor I obtained in the step 5) is subjected to reduced pressure distillation to obtain 242kg of distilled isopropanol and 7kg of residual liquid.

8) Adding liquid alkali into 7kg of residual liquid obtained in the step 7) to adjust the pH value to 10.5, distilling and recycling 6.36 kg of 2-methylpyridine, wherein the bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, wherein the refined isopropanol is about 240 kilograms, and the refined isopropanol returns to the step 5) for recycling.

Example 3, change the quality of the high residue amproline hydrochloride used in the step 1), namely, the ignition residue in the high residue amproline hydrochloride quality index is improved from 0.53 percent to 10.02 percent, and the rest of the reference examples 1 to 3 are carried out in sequence as follows:

1) putting 350kg of high-residue amproline hydrochloride into a 3000L dissolving kettle, putting 2500kg of amproline hydrochloride methanol mother liquor I obtained in the step 4) of the embodiment 1-3, closing a feeding port, opening an inlet and outlet cooling circulating water valve of a reflux condenser, introducing steam into a jacket for heating, when the temperature in the kettle reaches 72 ℃, discharging liquid drops at an outlet of the condenser, starting methanol reflux, sampling and observing, and completely dissolving the amproline hydrochloride to obtain an amproline hydrochloride methanol solution I.

The high residue amproline hydrochloride has the following quality indexes that the content (calculated by dry basis) of the amproline hydrochloride is 87.31 percent, the ignition residue is 10.02 percent, the 2-methylpyridine is 1.67 percent, and the rest is other impurities, and the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the methanol solution I of the aminopropyl amine hydrochloride obtained in the step 1) while the solution is hot (by adopting a bag filter), and obtaining about 2813kg of methanol solution II of the aminopropyl amine hydrochloride after impurity removal and about 37kg of solid residue.

3) 2813kg of the amproline hydrochloride methanol solution II obtained in the step 2) after impurity removal is immediately transferred into a crystallization kettle, and cooling water is introduced to reduce the temperature to 15-20 ℃ while stirring, so as to obtain crystallized amproline hydrochloride slurry.

4) And centrifugally drying the cooled and crystallized aminopropyl hydrochloride slurry obtained in the step 3) to obtain 320kg of aminopropyl hydrochloride wet product I and 2493kg of aminopropyl hydrochloride methanol mother liquor I.

5) And putting 320kg of the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding 320kg of isopropanol (namely the weight ratio of the wet amprolium hydrochloride I to the isopropanol is 1:1), stirring and pulping for 60min, and then carrying out centrifugal drying to obtain 319kg of wet amprolium hydrochloride II and 321kg of mother liquor I of the amprolium hydrochloride isopropanol.

6) And drying, crushing and packaging 319kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 303kg of finished product to be put in storage.

7) 321kg of alanine hydrochloride isopropanol mother liquor I obtained in the step 5) is subjected to reduced pressure distillation to obtain 314kg of distilled isopropanol and 7kg of residual liquid.

8) Adding liquid alkali into 7kg of residual liquid obtained in the step 6) to adjust the pH value to 10.5, distilling and recycling 6.2 kg of 2-methylpyridine, wherein the bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of the 2-methylpyridine is about 96-97%.

9) 314kg of isopropanol obtained by distillation in the step 7) is rectified and dehydrated by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, about 308 kg of isopropanol, and the refined isopropanol is returned to the step 5) for recycling.

Example 4, change the quality of the high residue amproline hydrochloride used in the step 1), namely, the ignition residue in the quality index of the high residue amproline hydrochloride is improved from 0.53% to 21.13%, and the rest of the reference examples 1 to 3 specifically comprises the following steps:

The quality index of the high residue amproline hydrochloride is as follows, the content of the amproline hydrochloride (calculated by dry basis) is 75.98%, the ignition residue is 21.13%, the 2-methylpyridine is 1.89%, and the rest is other impurities; the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 2772kg of an alanine hydrochloride methanol solution II after impurity removal and about 78kg of solid residues.

3) And 2) immediately transferring 2772kg of the amprolium hydrochloride methanol solution II subjected to impurity removal obtained in the step 2) into a crystallization kettle, introducing cooling water to cool down to 15-20 ℃ while stirring, and obtaining crystallized amprolium hydrochloride slurry.

4) And centrifugally drying the cooled and crystallized aminopropyl hydrochloride slurry obtained in the step 3) to obtain 279kg of aminopropyl hydrochloride wet product I and 2493kg of aminopropyl hydrochloride methanol mother liquor I.

5) 279kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) is put into a pulping kettle, 279kg of isopropanol is added, the mixture is stirred and pulped for 30min, and then centrifugal drying is carried out to obtain 277kg of wet product II of the aminopropyl amine hydrochloride and 281kg of mother liquor I of the aminopropyl amine hydrochloride isopropanol.

6) 277kg of the amprolium hydrochloride wet product II obtained in the step 5) is dried, crushed and packaged to obtain about 264kg of finished product to be put in storage.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 99.51% of amproline hydrochloride, 0.29% of residue, 0.15% of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.13 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) 281kg of alanine hydrochloride isopropanol mother liquor I obtained in the step 5) is subjected to reduced pressure distillation to obtain 274kg of distilled isopropanol and 7kg of residual liquid.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, wherein the weight of the refined isopropanol is about 268 kilograms, and the refined isopropanol returns to the step 5) for recycling.

Example 5, change the quality of the high residue amproline hydrochloride used in the step 1), namely, the ignition residue in the quality index of the high residue amproline hydrochloride is improved from 0.53 percent to 30.87 percent, and the rest of the reference examples 1-3 are carried out in sequence as follows:

The quality index of the high residue amproline hydrochloride is as follows, the content (calculated by dry basis) of the amproline hydrochloride is 66.32 percent, the ignition residue is 30.87 percent, the 2-methylpyridine is 1.81 percent, and the rest is other impurities; the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 2736kg of an alanine hydrochloride methanol solution II after impurity removal and about 114kg of solid residues.

3) And 2) immediately transferring 2736kg of the amprolium hydrochloride methanol solution II subjected to impurity removal obtained in the step 2) into a crystallization kettle, introducing cooling water to cool down to 15-20 ℃ while stirring, and obtaining crystallized amprolium hydrochloride slurry.

4) And centrifugally drying the cooled and crystallized aminopropyl hydrochloride slurry obtained in the step 3) to obtain 243kg of an aminopropyl hydrochloride wet product I and 2493kg of an aminopropyl hydrochloride methanol mother liquor I.

5) Putting 243kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) into a pulping kettle, adding 243kg of isopropanol, stirring and pulping for 30min, and then carrying out centrifugal drying to obtain 241kg of wet product II of the aminopropyl amine hydrochloride and 245kg of mother liquor I of the aminopropyl amine hydrochloride isopropanol.

6) Drying, crushing and packaging 241kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 229kg of finished product to be put in storage.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 99.56% of amproline hydrochloride, 0.27% of residue, 0.14% of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.11 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) 245kg of alanine hydrochloride isopropanol mother liquor I obtained in the step 5) is subjected to reduced pressure distillation to obtain 238kg of distilled isopropanol and 7kg of residual liquid.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, wherein the weight of the refined isopropanol is about 232 kilograms, and the refined isopropanol returns to the step 5) for recycling.

Example 6, change the quality of the high residue amproline hydrochloride used in the step 1), namely, the ignition residue in the quality index of the high residue amproline hydrochloride is improved from 0.53 percent to 40.12 percent, and the dosage of the methanol is reduced from 2250kg to 1250kg, the rest is equal to the example 1-1, and the following steps are carried out in sequence:

1) 500kg of high-residue amprolium hydrochloride was put into a 3000L dissolution vessel, and 1250kg of methanol was put into the vessel (i.e., the weight ratio of high-residue amprolium hydrochloride to methanol was 1: 2.5), closing a feed port, opening an inlet and outlet cooling circulating water valve of a reflux condenser, introducing steam into a jacket for heating, when the temperature in the kettle reaches about 72 ℃, allowing liquid drops to be formed at an outlet of the condenser, starting methanol reflux, sampling and observing, and completely dissolving the amproline hydrochloride to obtain an amproline hydrochloride methanol solution I.

The high residue amproline hydrochloride has the following quality indexes that the content (calculated by dry basis) of the amproline hydrochloride is 56.99 percent, the ignition residue is 40.12 percent, the 2-methylpyridine is 1.89 percent, and the rest is other impurities, and the appearance is earthy yellow; the above percentages are mass%.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 1547kg of alanine hydrochloride methanol solution II after impurity removal and 203kg of solid residue.

3) Transferring 1547kg of the amproline hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle immediately, introducing cooling water to cool down to 15-20 ℃ while stirring, and obtaining crystallized amproline hydrochloride slurry.

4) And centrifugally drying the amproline hydrochloride slurry cooled and crystallized in the step 3) to obtain 173kg of amproline hydrochloride wet product I and 1374kg of amproline hydrochloride methanol mother liquor I.

5) 173kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) is put into a pulping kettle, 173kg of isopropanol is added, the mixture is stirred and pulped for 30min, and then centrifugal drying is carried out to obtain 171kg of wet product II of the aminopropyl amine hydrochloride and 175kg of mother liquor I of the aminopropyl amine hydrochloride isopropanol.

6) And drying, crushing and packaging 171kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 162kg of finished product to be stored.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 99.60% of amproline hydrochloride, 0.25% of ignition residue, 0.14% of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.11 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) Carrying out reduced pressure distillation on 175kg of the alanine isopropyl alcohol hydrochloride mother liquor I obtained in the step 5) to obtain 167kg of distilled isopropyl alcohol and 8kg of residual liquid.

8) Adding liquid alkali into 8kg of residual liquid obtained in the step 6) to adjust the pH value to 10.5, distilling and recovering 7.3 kg of 2-methylpyridine, wherein the bottom liquid of the distillation kettle can enter a sewage station for treatment according to a conventional mode.

The purity of the 2-methylpyridine is about 96-97%.

9) Rectifying the isopropanol obtained by distillation in the step 7), and dehydrating by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, wherein the refined isopropanol is about 165 kilograms, and the refined isopropanol returns to the step 5) for recycling.

Comparative examples 1-1 to 1-5, the high residue amproline hydrochloride used in examples 1-1, 2 and 4-6 was purified by the prior art (for example, the invention patent of 201510770969.1 entitled "method for producing high purity granular amproline hydrochloride"), respectively, and specifically included the following steps:

1) adding 150L of pure water into a 1000L dissolving and decolorizing kettle at room temperature (25 ℃), stirring, weighing 150kg of high-residue aminopropyl hydrochloride, and putting the high-residue aminopropyl hydrochloride into the dissolving and decolorizing kettle for dissolving to obtain 300kg of aminopropyl hydrochloride solution I.

The quality of the high residue aminoproline hydrochloride raw material used in comparative examples 1-1 to 1-5 is shown in Table 1:

high residue aminoproline hydrochloride feed for use in Table 1, comparative examples 1-1 to comparative examples 1-5

2) Opening a steam valve, heating 300kg of the aminopropyl hydrochloride solution I obtained in the step 1) to 50-60 ℃, adding 7.5kg of powdered activated carbon, stirring, keeping the temperature, decoloring and removing impurities for 30 minutes, then carrying out suction filtration to remove the activated carbon, passing the clear solution obtained by suction filtration through a polytetrafluoroethylene precision filter with the aperture of 0.45 micron, and simultaneously leaching the activated carbon by using 5L of pure water to finally obtain 300kg of decolored aminopropyl hydrochloride solution II and 12.5kg of activated carbon waste residues.

3) Pumping 300kg of decolorized aminopropyl hydrochloride solution II obtained in the step 2) into a 3000L distillation crystallization kettle, adding 1200L of organic solvent isopropanol under stirring, beginning 500L for 10 minutes, finishing the subsequent 700L within 1-2 hours, and slowly precipitating aminopropyl hydrochloride crystals. After the isopropanol is added, continuously stirring for growing the crystals for 1 hour, and then centrifugally drying. And (3) after the mother liquor is dried, leaching with an organic solvent isopropanol, wherein the dosage of the isopropanol used for leaching is 60L, and finally obtaining a refined amprolium hydrochloride wet product I and the mother liquor I.

4) And 3) evaporating and concentrating the mother liquor I obtained in the step 3) under reduced pressure (the vacuum degree is 0.065-0.075MPa) until crystals are separated out, adding 400L of isopropanol into the concentrated solution again for crystallization, wherein the dropping speed of the isopropanol is the same as that in the step 3), continuously stirring for crystallization for 1 hour after the crystallization is finished, and then centrifuging and drying. And after the mother liquor is dried, leaching with isopropanol, wherein the dosage of the isopropanol used for leaching is 10L, and obtaining a refined amprolium hydrochloride wet product II and the mother liquor II.

5) Uniformly mixing the refined wet product I of the aminopropyl amine hydrochloride obtained in the step 3) with the refined wet product II of the aminopropyl amine hydrochloride obtained in the step 3), drying, crushing and screening, wherein the detection results are shown in the following table 2:

TABLE 2 analysis results of experimental samples of comparative examples 1-1 to comparative examples 1-5

As can be seen from the data in Table 2, the sample residue obtained by purifying high residue amproline hydrochloride by the method taught in the prior art is far higher than the specified requirement.

Comparative example 2, the step 5) of pulping isopropanol in the example 1-1 is omitted, namely, the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) is directly dried, and other operations are as in the example 1-1;

namely, 310kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) of the embodiment 1 is dried (dried at 105 ℃ for about 3-5 hours), crushed (screened by a 40-mesh screen) and packaged to obtain 281kg of finished products to be put in storage.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 97.43% of amproline hydrochloride, 0.59% of residue, 0.36% of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.12 percent, the quality does not meet the requirement of Chinese animal pharmacopoeia (2015), and the obtained product is easy to agglomerate.

The wet product I of the aminopropyl amine hydrochloride is not pulped and washed by isopropanol, and the obtained product residue and related impurities exceed the requirements of Chinese veterinary pharmacopoeia.

Comparative example 3, the amount of beating isopropanol in step 5) of examples 1-3 was increased from 345kg to 690kg, i.e. the weight ratio of amproline hydrochloride wet product I to isopropanol was 1:2, and the other equivalents were the same as in examples 1-3, as follows:

steps 1) to 4) were the same as in examples 1 to 3;

5) putting 345kg of the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding 690kg of isopropanol (namely the weight ratio of the wet amprolium hydrochloride I to the isopropanol is 1:2), stirring and pulping for 30min, and then carrying out centrifugal drying to obtain 335kg of wet amprolium hydrochloride II and 700kg of mother liquor of the amprolium hydrochloride isopropanol I.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 99.52 percent of amproline hydrochloride, 0.26 percent of ignition residue, 0.14 percent of 2-methylpyridine and the balance of other impurities; the drying weight loss is 0.12 percent, and all indexes meet the requirements of Chinese animal pharmacopoeia (2015).

7) And 6kg of residual liquid and 694kg of distilled isopropanol are obtained by distilling 700kg of the alanine hydrochloride isopropanol mother liquor I obtained in the step 5) under reduced pressure.

8) Adding liquid alkali into 6kg of residual liquid obtained in the step 6) to adjust the pH value to 10.5, distilling and recycling 5.2 kg of 2-methylpyridine, and feeding the bottom liquid of the distillation kettle into a sewage station for treatment.

9) 694kg of isopropanol obtained by distillation in the step 7) is rectified and dehydrated by an inorganic vaporization permeable membrane to obtain refined isopropanol with the water content of less than 0.5 percent, about 671 kg of isopropanol, and the refined isopropanol is returned to the step 5) for recycling.

Although the pulping amount of the isopropanol in the step 5) is increased from 345kg to 690kg (the dosage of the isopropanol is increased by 1 time), the quality index of the final product is not improved, and the subsequent recovery and dehydration cost of the isopropanol is increased.

Comparative example 4, the amount of methanol used in step 1) of example 2 is increased from 2250kg to 4500kg, the amount of high residue amproline hydrochloride is reduced from 500kg to 350kg, and the materials are completely dissolved in methanol, and other operations refer to example 2, specifically as follows:

1) 350kg of high residue amprolium hydrochloride (same as in example 2) was charged into a 5000L dissolution vessel, and 4500kg of methanol (i.e., the weight ratio of high residue amprolium hydrochloride to methanol was about 1: 12.86), closing the feed port, opening an inlet and outlet cooling circulating water valve of a reflux condenser, introducing steam into the jacket for heating, introducing liquid drops at the outlet of the condenser when the temperature in the kettle reaches 72 ℃, starting methanol reflux, sampling and observing, and completely dissolving the amproline hydrochloride to obtain an amproline hydrochloride methanol solution I.

2) Filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot (by adopting a bag filter) to obtain 4850kg of an alanine hydrochloride methanol solution II after impurity removal and 0.3kg of solid residue.

Note: since the amount of solid residue produced was very small and negligible, the methanol solution II of amproline hydrochloride after impurity removal was still 4850kg here.

3) And 3) immediately transferring 4850kg of the amprolium hydrochloride methanol solution II subjected to impurity removal obtained in the step 2) into a crystallization kettle, introducing cooling water to cool down to 15-20 ℃ while stirring, and obtaining crystallized amprolium hydrochloride slurry.

4) And centrifugally drying the amproline hydrochloride slurry cooled and crystallized in the step 3) to obtain 88kg of amproline hydrochloride wet product I and 4762kg of amproline hydrochloride methanol mother liquor I.

5) Putting 88kg of the wet product I of the aminopropyl amine hydrochloride obtained in the step 4) into a pulping kettle, adding 88kg of isopropanol, stirring and pulping for 60min, and then carrying out centrifugal drying to obtain 86kg of wet product II of the aminopropyl amine hydrochloride and 90kg of mother liquor I of the aminopropyl amine hydrochloride isopropanol.

6) And drying, crushing and packaging 86kg of the amprolium hydrochloride wet product II obtained in the step 5) to obtain 82kg of finished product to be put in storage.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: the content of the amproline hydrochloride is 97.64 percent, the ignition residue is 1.79 percent, the content of the 2-methylpyridine is 0.14 percent, the balance is other impurities, and the drying weight loss is 0.12 percent.

The firing residue of the refined amproline hydrochloride finished product obtained in the comparative example 4 does not meet the requirements of Chinese veterinary pharmacopoeia (2015), and the single yield is obviously reduced; and the content of the amproline hydrochloride is not as good as that of the invention. It is shown that excessive methanol during the dissolution process affects the final refining effect.

Comparative example 5, the cooling crystallization of step 3) of comparative example 4 was changed to the conventional methanol all-solution recrystallization method:

transferring 4850kg of the amprolium hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle immediately, heating, evaporating and concentrating, stopping evaporating and concentrating when the material begins to crystallize, introducing cooling water for cooling under stirring, and cooling to 15-20 ℃ to obtain crystallized amprolium hydrochloride slurry.

And then, carrying out centrifugal drying on the cooled and crystallized amproline hydrochloride slurry to obtain 240kg of an amproline hydrochloride wet product I.

And finally, drying, crushing and packaging 240kg of the amproline hydrochloride wet product I to obtain 216kg of finished product to be stored.

The quality indexes of the obtained amproline hydrochloride finished product are as follows: 91.68 percent of aminoproline hydrochloride, 7.14 percent of residue, 0.36 percent of 2-methylpyridine and the balance of other impurities, wherein the drying weight loss is 0.15 percent, and the index does not meet the requirement of Chinese animal pharmacopoeia (2015).

The conventional methanol full-solution recrystallization process is adopted, the high-residue amproline hydrochloride cannot be purified, and the obtained product residue far exceeds the standard requirement.

Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.

Claims

1. The method for purifying the high-residue amproline hydrochloride is characterized by comprising the following steps of:

1) dissolving the high residue amproline hydrochloride in methanol at the reflux temperature or the amproline hydrochloride methanol mother liquor I obtained in the subsequent step 4), so that the amproline hydrochloride contained in the high residue amproline hydrochloride is completely dissolved to obtain the amproline hydrochloride methanol solution I;

the weight ratio of the high-residue amprolium hydrochloride to the methanol is 1: 2.5-4.5;

or, the weight ratio of the high-residue amprolium hydrochloride to the amprolium hydrochloride methanol mother liquor I obtained in the step 4) is 1 (7 +/-0.5);

the high residue amproline hydrochloride quality indexes are as follows: the content of the alanine hydrochloride is more than 50 percent calculated by dry basis; the ignition residue is more than 0.5 percent; the appearance is earthy yellow to grey brown; the above percentages are mass%;

2) filtering the alanine hydrochloride methanol solution I obtained in the step 1) while the solution is hot to respectively obtain an alanine hydrochloride methanol solution II and solid residues after impurity removal;

3) transferring the amprolium hydrochloride methanol solution II obtained in the step 2) after impurity removal into a crystallization kettle, and cooling and crystallizing to obtain amprolium hydrochloride slurry after cooling and crystallization;

5) putting the wet amprolium hydrochloride I obtained in the step 4) into a pulping kettle, adding isopropanol for pulping, and then centrifugally drying to obtain an amprolium hydrochloride wet product II and an amprolium hydrochloride isopropanol mother liquor I;

the weight ratio of the amprolium hydrochloride wet product I to the isopropanol is 1: 0.5-1;

6) drying and crushing the wet product II of the aminopropyl amine hydrochloride obtained in the step 5) to obtain the aminopropyl amine hydrochloride.

2. The method for purifying high residue amproline hydrochloride according to claim 1, characterized by further comprising the following step 7):

distilling the alanine isopropyl alcohol hydrochloride mother liquor I obtained in the step 5) to obtain an isopropanol crude product and a residual liquid, rectifying and dehydrating the isopropanol crude product to obtain recovered isopropanol, and returning to the step 5) for recycling.

3. The method for purifying high residue amproline hydrochloride according to claim 2, wherein: adding alkali into the residual liquid obtained in the step 7), adjusting the pH value to 10-10.5, and distilling to recover the 2-methylpyridine.