CN116764262B - A crystallization method and device for preparing 7-ACT - Google Patents
A crystallization method and device for preparing 7-ACTInfo
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- CN116764262B CN116764262B CN202310721900.4A CN202310721900A CN116764262B CN 116764262 B CN116764262 B CN 116764262B CN 202310721900 A CN202310721900 A CN 202310721900A CN 116764262 B CN116764262 B CN 116764262B
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Abstract
The invention relates to a crystallization method and a crystallization device for 7-ACT preparation, wherein the device comprises the following steps of 1) cooling hydrolysate to 0-10 ℃, separating the hydrolysate into solution A and solution B, adding alkali into the solution A to adjust the pH value to a, adjusting the pH value of the solution B to B, controlling the pH value to be less than or equal to 0.5 (a-B) to less than or equal to 1, stopping adding alkali when crystal precipitation of the solution A is observed, 2) culturing the solution A for 30min, mixing the solution A with the solution B, adding alkali to adjust the pH value to 3.0-4.0, keeping the temperature below 10 ℃, stirring for crystallization, and washing the crystal after suction filtration. The invention can realize the accurate control of the supersaturation degree in the solution nucleation stage, is beneficial to the control of nucleation quality in the crystallization process, and further controls the crystallization quality. The invention can improve the crystallization quality of 7-ACT, thereby improving the product yield and the product quality.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a crystallization method and device for 7-ACT preparation.
Background
The 7-ACT is an intermediate for preparing ceftriaxone sodium, and the process is generally carried out by taking 7-ACA and triazinic acid as raw materials, and taking boron trifluoride as a catalyst to react in a system taking acetonitrile as a solvent. Although some new synthesis processes are disclosed in the prior art, the hydrolysis liquid is crystallized, filtered and separated by suction and then dried to obtain the product. In an acidic system, 7-ACT has high solubility in an aqueous phase and is lower than 5g/L at a pH of 3-4, so that crystallization can be realized by adjusting the pH value to 3-4 by adding alkali.
The adjusting process of the pH value during crystallization greatly affects the crystal grain size. If the control is improper, the crystallization granularity is too fine, the suction filtration difficulty is high, the product loss is large, and the yield is reduced. And the raw materials and the products of the 7ACA have high value, and the yield is reduced, so that the economic benefit is greatly influenced. In addition, too fine granularity can also lead to high moisture content after suction filtration, long drying time consumption, and long drying time affects the quality of products greatly, and the color grade of the products does not reach the standard.
Disclosure of Invention
Aiming at the problems, the invention adopts the following specific scheme:
a crystallization method for 7-ACT preparation, comprising the steps of:
1) Cooling the hydrolysate to 0-10 ℃, separating the hydrolysate into a solution A and a solution B, adding alkali into the solution A to adjust the pH value to a, adjusting the pH value of the solution B to B, controlling the a-B to be more than or equal to 0.5 and less than or equal to 1, and stopping adding alkali when the solution A is observed to have crystals separated out;
2) After growing the crystal of the solution A for 30min, mixing the solution A with the solution B, adding alkali to adjust the pH value to 3.0-4.0, keeping the temperature below 10 ℃, stirring for crystallization, and washing the crystal after suction filtration.
In crystallization, if the supersaturation degree is controlled improperly, the supersaturation degree is too large, the nucleation speed is too high, the nucleation quantity is easy to be large, the granularity is small, and the crystallized particles are too fine. In the crystallization of 7-ACT, the pH is adjusted by adding alkali to lower the solubility of 7-ACT, thereby reaching a supersaturation state. In actual production, when crystal precipitation occurs in the solution, judging that the solution just reaches a supersaturated state, and stopping adding alkali at the moment to control the supersaturation degree of the solution. The method has the advantages that the control difficulty is high, the solubility of 7-ACT in water is greatly reduced by a large degree when the pH value is close to 2, and the supersaturation degree is possibly high when crystal precipitation is observed. In addition, the pH value change condition of the solution can be monitored through the pH meter, when the alkali is added, a diffusion period exists, when the volume of the crystallization tank is large, the pH value difference of different positions is large, the pH meter can only monitor the local pH value, the condition of the whole pH value can not be reflected, and the supersaturation degree of the solution can not be accurately controlled.
According to the scheme, the hydrolysate to be crystallized is divided into two parts, the pH difference value of the two parts of solutions is controlled, wherein the part of solution with higher pH value is used for nucleation, the part of solution with lower pH value is used for controlling the supersaturation degree in a contrasting manner, and the method is beneficial to improving the nucleation quality and the crystallization quality.
Wherein the solution A is directly adjusted to pH value by alkali liquor, and the alkali liquor can be ammonia water or sodium hydroxide solution. The solution B can also be directly regulated by alkali liquor, and can also be regulated by the solution A with regulated pH value.
Preferably, in step 1), (a-b) is controlled at 0.5. The smaller the value is, the more beneficial to controlling the supersaturation degree of the solution A, and when the value is lower than 0.5, the actual operation difficulty is high and cannot be realized.
Preferably, the mass ratio of the solution A to the solution B is 5-7:3. Solution A was used for nucleation in a proportion which ensures that the mixture had an appropriate amount of nuclei.
Further, in the step 1), the hydrolysis liquid is firstly cooled to 0-5 ℃, when the solution B is also precipitated with crystals, alkali addition is stopped, and the solution A and the solution B are synchronously heated until the crystals in the solution B disappear. Considering the difficulty of practical operation, it is possible that crystals are precipitated in solution B when solution a is observed, indicating that the supersaturation degree of solution a is already large at this time, and the supersaturation degree can be reduced by appropriately increasing the temperature of the solution.
In order to realize the method of the invention, the invention discloses a crystallization device for 7-ACT preparation, which comprises a main tank body and an auxiliary tank body which are connected in series, wherein the main tank body is provided with an alkali liquor feeding pipe, the auxiliary tank body is communicated with the main tank body through a bottom flow pipe, stirring paddles, a pH meter and a thermometer are arranged in the main tank body and the auxiliary tank body, and water cooling jackets are arranged outside the main tank body and the auxiliary tank body.
During crystallization, a part of the hydrolysate enters the main tank body as a solution A, and the other part enters the auxiliary tank body as a solution B, and a pH meter and a thermometer are used for monitoring the pH value and the temperature of the solution. The alkali liquor is added into the solution A, after the pH value of the solution A is raised, a part of the solution A enters the solution B along the underflow pipe, and the pH value of the solution B is raised along with the underflow pipe. The main tank body is used for nucleating, and the auxiliary tank body is used for comparing and controlling the supersaturation degree.
The crystallization device for preparing 7-ACT comprises an outer tank body and an inner tank body, wherein the inner tank body is arranged in the outer tank body, an alkali liquor feeding pipe is arranged in the inner tank body, an opening capable of being opened and closed is arranged at the lower part of the inner tank body, pH meters and thermometers are arranged in and outside the inner tank body, stirring paddles are arranged in the inner tank body, and a water cooling jacket is arranged outside the outer tank body.
The solution A enters the inner tank body and the solution B enters the area between the inner tank body and the outer tank body. The scheme is beneficial to synchronously controlling the temperature of the solution A and the solution B.
Further, the inner tank body comprises a cylinder body and a base, the base is fixedly connected with the outer tank body, and the cylinder body is provided with a lifting mechanism. When the cylinder descends and contacts with the base, the inner tank body and the outer tank body are isolated from each other, and when the cylinder ascends and is separated from the base, the inner tank body and the outer tank body are communicated.
The invention has the advantages that the invention can realize the accurate control of the supersaturation degree in the solution nucleation stage, is beneficial to the control of nucleation quality in the crystallization process, and further controls the crystallization quality. The invention can improve the crystallization quality of 7-ACT, thereby improving the product yield and the product quality.
Drawings
The invention will be further described with reference to the drawings and examples.
FIG. 1 is a schematic diagram showing the structure of a crystallization apparatus in example 5.
FIG. 2 is a schematic structural view of the crystallization apparatus in example 6.
Detailed Description
Example 1
Adding 7-ACA and triazinic acid into the mixed solution of acetonitrile and boron trifluoride acetonitrile complex in proportion, stirring and reacting completely, cooling to 0-10 ℃, adding purified water for hydrolysis, and extracting to obtain hydrolysate. The hydrolysis liquid is divided into a solution A and a solution B according to a mass ratio of 5:3, ammonia water is added into the solution A in a flowing way, the solution B is used for adjusting the pH value by the solution A, when the crystal precipitation of the solution A is observed, the ammonia water is stopped being added, the pH value of the solution A is 2.2, the pH value of the solution B is 1.7, and no crystal is precipitated in the solution B. After the solution A grows crystals for 30min, mixing the solution A with the solution B, stirring and crystallizing for 1 hour, carrying out suction filtration, washing crystals, vacuum drying until the water content is less than or equal to 1%, weighing, calculating the mass yield, and detecting the granularity and color grade indexes.
Example 2
Adding 7-ACA and triazinic acid into the mixed solution of acetonitrile and boron trifluoride acetonitrile complex in proportion, stirring and reacting completely, cooling to 0-10 ℃, adding purified water for hydrolysis, and extracting to obtain hydrolysate. The hydrolysis liquid is divided into a solution A and a solution B according to the mass ratio of 7:3, ammonia water is added into the solution A in a flowing way, the solution B is used for adjusting the pH value by the solution A, when the crystal precipitation of the solution A is observed, the ammonia water is stopped being added, the pH value of the solution A is 2.5, the pH value of the solution B is 1.3, and no crystal is precipitated in the solution B. After the solution A grows crystals for 30min, mixing the solution A with the solution B, stirring and crystallizing for 1 hour, carrying out suction filtration, washing crystals, vacuum drying until the water content is less than or equal to 1%, weighing, calculating the mass yield, and detecting the granularity and color grade indexes.
Example 3
Adding 7-ACA and triazinic acid into the mixed solution of acetonitrile and boron trifluoride acetonitrile complex in proportion, stirring and reacting completely, cooling to 0-10 ℃, adding purified water for hydrolysis, and extracting to obtain hydrolysate. The hydrolysis liquid is divided into a solution A and a solution B according to the mass ratio of 6:3, ammonia water is added into the solution A in a flowing way, the solution B is used for adjusting the pH value by the solution A, when the crystal precipitation of the solution A is observed, the ammonia water is stopped being added, the pH value of the solution A is 2.6, the pH value of the solution B is 2.1, and the crystal precipitation also occurs in the solution B. After the solution A grows crystals for 30min, mixing the solution A with the solution B, stirring and crystallizing for 1 hour, carrying out suction filtration, washing crystals, vacuum drying until the water content is less than or equal to 1%, weighing, calculating the mass yield, and detecting the granularity and color grade indexes.
Example 4
Adding 7-ACA and triazinic acid into the mixed solution of acetonitrile and boron trifluoride acetonitrile complex in proportion, stirring and reacting completely, cooling to 0-10 ℃, adding purified water for hydrolysis, and extracting to obtain hydrolysate. The hydrolysis liquid is cooled to 0-5 ℃ firstly, then is divided into a solution A and a solution B according to the mass ratio of 6:3, ammonia water is added into the solution A in a flowing way, the solution B is used for adjusting the pH value of the solution A, when the solution A is observed to be precipitated, the ammonia water is stopped being added, the pH value of the solution A is 2.3, the pH value of the solution B is 1.7, and the solution B is also precipitated. The temperature of the solution A and the solution B are increased by 3 ℃, crystals in the solution B are redissolved and disappear, and crystals still exist in the solution A to be separated out. After the solution A grows crystals for 30min, mixing the solution A with the solution B, stirring and crystallizing for 1 hour, carrying out suction filtration, washing crystals, vacuum drying until the water content is less than or equal to 1%, weighing, calculating the mass yield, and detecting the granularity and color grade indexes.
Comparative example 1
Adding 7-ACA and triazinic acid into the mixed solution of acetonitrile and boron trifluoride acetonitrile complex in proportion, stirring and reacting completely, cooling to 0-10 ℃, adding purified water for hydrolysis, and extracting to obtain hydrolysate. Ammonia water was added to the hydrolysate until the pH was 2.6, and crystals were observed to precipitate, and the addition of ammonia water was stopped. After crystal growth for 30min, stirring and crystallizing for 1 h, carrying out crystal washing after suction filtration, vacuum drying until the water content is less than or equal to 1%, weighing, calculating the quality yield, and checking the appearance quality.
The results of examples 1-4 and comparative example 1 are compared in the following table:
| Yield is good | Appearance of | |
| Example 1 | 125.3% | White color |
| Example 2 | 122.5% | White color |
| Example 3 | 122.0% | Yellow color |
| Example 4 | 126.5% | White color |
| Comparative example 1 | 121.7% | Yellow color |
As can be seen from comparison, the yield of examples 1-3 fluctuates greatly, and the supersaturation of the solution is not effectively controlled in the nucleation of example 3, so that the yield is obviously reduced, the drying time of the crystals is long, and the appearance of the crystals is yellowish after the drying. Example 4 the control method is improved, the supersaturation degree of the solution during nucleation is effectively controlled, the yield is improved, and the appearance of the product is normal. The comparative example is carried out according to the conventional process, and also because the supersaturation degree cannot be effectively controlled, the crystallization quality is poor, the yield is low, the drying time is long, and the appearance is yellowish.
Example 5
The embodiment is used for explaining a crystallization device for 7-ACT preparation, as shown in figure 1, and comprises a main tank body 1 and an auxiliary tank body 2 which are connected in series, wherein the main tank body is provided with an alkali liquor feeding pipe 3, the auxiliary tank body is communicated with the main tank body through a bottom flow pipe 4, stirring paddles, a pH meter 5 and a thermometer 6 are arranged in the main tank body and the auxiliary tank body, and water cooling jackets are arranged outside the main tank body and the auxiliary tank body. Peristaltic pumps 7 are arranged on the alkali liquor feeding pipe and the bottom flow pipe and are used for controlling feeding amount. The water cooling jacket can be filled with circulating cooling water to control the temperature of the solution in the tank body.
During crystallization, a part of the hydrolysate enters the main tank body as a solution A, and the other part enters the auxiliary tank body as a solution B, and a pH meter and a thermometer are used for monitoring the pH value and the temperature of the solution. The alkali liquor is added into the solution A, after the pH value of the solution A is raised, a part of the solution A enters the solution B along the underflow pipe, and the pH value of the solution B is raised along with the underflow pipe. The main tank body is used for nucleating, and the auxiliary tank body is used for comparing and controlling the supersaturation degree.
Example 6
This example is for illustrating another crystallization apparatus for 7-ACT preparation, as shown in FIG. 2, comprising an outer tank 8 and an inner tank 9, wherein the inner tank 9 is disposed inside the outer tank, the inner tank 9 is provided with an alkali feeding pipe 3, the lower part of the inner tank is provided with an openable opening, the inner tank is internally and externally provided with a pH meter 5 and a thermometer 6, the inner tank is internally provided with a stirring paddle, and the outer tank is externally provided with a water cooling jacket.
The solution A enters the inner tank body and the solution B enters the area between the inner tank body and the outer tank body. The scheme is beneficial to synchronously controlling the temperature of the solution A and the solution B.
The inner tank 9 comprises a cylinder 901 and a base 902, the base is fixedly connected with the outer tank, the cylinder is provided with a lifting mechanism, and the lifting mechanism adopts a lead screw 10 driving mode. The inner tank 9 is isolated from the outer tank 8 when the cylinder 901 is lowered and brought into contact with the base 902, and the inner tank 9 communicates with the outer tank 8 when the cylinder 901 is raised and separated from the base 902. The opening of the lower part of the inner tank body is controlled by the lifting height, the inner tank body slightly rises during nucleation, and the inner tank body rises to the upper limit during crystallization, so that the inside and the outside are completely communicated.
Claims (4)
1. A crystallization method for 7-ACT preparation, comprising the steps of:
1) Cooling the hydrolysate to 0-10 ℃, dividing the hydrolysate into a solution A and a solution B, adding alkali into the solution A to adjust the pH value to a, adjusting the pH value of the solution B to B, controlling the pH value to be less than or equal to 0.5 (a-B) to less than or equal to 1, and stopping adding alkali when crystal precipitation of the solution A is observed;
2) After growing the crystal of the solution A for 30min, mixing the solution A with the solution B, adding alkali to adjust the pH value to 3.0-4.0, keeping the temperature below 10 ℃, stirring for crystallization, and washing the crystal after suction filtration.
2. The crystallization method according to claim 1, wherein (a-b) is controlled to 0.5 in the step 1).
3. A crystallization method for 7-ACT according to claim 1, wherein the mass ratio of the solution A to the solution B is 5-7:3.
4. The crystallization method according to claim 1, wherein in step 1), the hydrolysis solution is cooled to 0-5 ℃ and when the solution B is observed to be precipitated, the alkali addition is stopped, and the solution A and the solution B are heated synchronously until the crystals in the solution B disappear.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108939599A (en) * | 2018-07-25 | 2018-12-07 | 天津大学 | A kind of self-loopa crystallizer and multistage continuous crystallisation process |
| CN110025973A (en) * | 2019-05-15 | 2019-07-19 | 青海盐湖工业股份有限公司 | A kind of crystallizer |
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| JPH05111602A (en) * | 1991-10-22 | 1993-05-07 | Nikko Kyodo Co Ltd | Crystallizer and method thereof |
| DE102014104689B3 (en) * | 2014-04-02 | 2015-09-24 | Gea Niro Pt B.V. | Multi-stage system for freezing concentration |
| CN107551597A (en) * | 2017-09-05 | 2018-01-09 | 广州百兴网络科技有限公司 | A kind of cerium sulphate crystal method |
| CN111760321A (en) * | 2020-07-20 | 2020-10-13 | 河北美邦工程科技股份有限公司 | Caprolactam crystallization integrated system and method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108939599A (en) * | 2018-07-25 | 2018-12-07 | 天津大学 | A kind of self-loopa crystallizer and multistage continuous crystallisation process |
| CN110025973A (en) * | 2019-05-15 | 2019-07-19 | 青海盐湖工业股份有限公司 | A kind of crystallizer |
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