CN211445580U - Production device for different crystal forms of valaciclovir hydrochloride - Google Patents
Production device for different crystal forms of valaciclovir hydrochloride Download PDFInfo
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- CN211445580U CN211445580U CN201922390260.5U CN201922390260U CN211445580U CN 211445580 U CN211445580 U CN 211445580U CN 201922390260 U CN201922390260 U CN 201922390260U CN 211445580 U CN211445580 U CN 211445580U
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Abstract
The utility model relates to a apparatus for producing of different crystal forms of valaciclovir hydrochloride, including reation kettle, reation kettle passes through the pipeline and connects gradually with first filter equipment, crystallization kettle, second filter equipment, first desicator and refined cauldron, and refined cauldron bottom bin outlet is respectively through pipeline and first heat exchanger and second heat exchanger intercommunication, and the second heat exchanger passes through pipeline and third heat exchanger and fourth heat exchanger and communicates in proper order, and first heat exchanger and fourth heat exchanger discharge gate communicate with vacuum filter through the pipeline respectively, refined cauldron top constitutes the return circuit with condenser, vapour and liquid separator in proper order, and the pipeline of vapour and liquid separator bottom inserts the inside liquid level below of refined cauldron, refined cauldron pan feeding mouth is equipped with the crystallization solvent admission pipe, vacuum filter's filter residue discharge gate and second desicator pan feeding mouth intercommunication. The utility model discloses can adopt the valaciclovir hydrochloride of four different crystal types of production under the same raw and other materials system, practice thrift manufacturing cost.
Description
Technical Field
The utility model relates to a chemistry technical field specifically provides a valaciclovir hydrochloride's reaction unit.
Background
Valacyclovir hydrochloride is a new generation antiviral drug developed by the Kulansu Schker company after acyclovir, passes through the American FDA evaluation in 6 months in 1995, and is mainly used for treating varicella, herpes zoster and herpes simplex virus infections I and II, including initial and recurrent genital herpes virus infections. Drug crystallization has become a main technical process in the drug production process, and the difference of drug crystal forms can cause the change of drug performance and quality, thereby affecting the safety and effectiveness of drug preparations and leading to the significant difference of clinical drug effects. And the research on the production process of different crystal forms can help the stability of the production process. Currently, there are different methods for producing valacyclovir hydrochloride in different crystal forms, for example, examples 24 to 27 of patent "CN 1922179A" also disclose a method for preparing valacyclovir hydrochloride in anhydrous crystal form i, in which valacyclovir hydrochloride in anhydrous crystal form i is named as "valacyclovir hydrochloride form iii", and valacyclovir hydrochloride hydrate is converted into anhydrous crystal form i in a specific solvent normal gas atmosphere. US6107302 introduces a preparation method of valacyclovir hydrochloride anhydrous crystal form I, which comprises the steps of firstly preparing a dry valacyclovir hydrochloride hydrate product, then mixing the dry valacyclovir hydrochloride hydrate product with ethanol with the weight of 15-40% of the hydrate, heating the mixture in a closed container to 50-70 ℃, keeping the temperature for a period of time in an ethanol steam atmosphere, and then directly reducing the pressure and drying the mixture to obtain the valacyclovir anhydrous crystal form I. Therefore, the valaciclovir hydrochloride with different crystal forms has different production processes and increases the production cost for enterprises.
Disclosure of Invention
The utility model aims to solve the technical problem that a reaction unit of valaciclovir hydrochloride is provided, can adopt the valaciclovir hydrochloride of four different crystal types of production under the same raw and other materials system.
The utility model adopts the technical proposal that:
the utility model provides a production device of different crystal forms of valaciclovir hydrochloride, includes reation kettle, reation kettle passes through the pipeline and connects gradually with first filter equipment, crystallization kettle, second filter equipment, first desicator and refined cauldron, and refined cauldron bottom bin outlet communicates with first heat exchanger and second heat exchanger through pipeline respectively, and the second heat exchanger communicates in proper order with third heat exchanger and fourth heat exchanger through the pipeline, and first heat exchanger and fourth heat exchanger discharge gate communicate with vacuum filter through the pipeline respectively, refined cauldron top constitutes the return circuit with condenser, vapour and liquid separator in proper order, and the pipeline of vapour and liquid separator bottom inserts the inside liquid level below of refined cauldron, refined cauldron pan feeding mouth is equipped with the crystallization solvent admission pipe, vacuum filter's filter residue discharge gate and second desicator pan feeding mouth intercommunication.
Preferably, a nitrogen inlet pipe is arranged at the bottom of the reaction kettle and communicated with a nitrogen tank, a feeding port above the reaction kettle is respectively communicated with the methanol tank, the CBZ-L-valine-acyclovir raw material tank, the catalyst preparation tank, the formic acid tank and the concentrated hydrochloric acid tank, and a feeding port of the catalyst preparation tank is communicated with the methanol tank.
Preferably, the crystallization kettle is provided with a propanol inlet pipe.
Preferably, the upper part of the first dryer is communicated with the first buffer tank and the first vacuum pump in sequence through pipelines.
Further preferably, the upper part of the first dryer is communicated with a liquid nitrogen tank through a pipeline.
Preferably, the upper part of the second dryer is communicated with a second buffer tank and a second vacuum pump in sequence through pipelines.
Preferably, a return pipe of the condenser communicated with the gas-liquid separator is inserted into the gas-liquid separator, and an isopropanol recovery pipe is arranged on the outer side of the gas-liquid separator and above the bottom of the return pipe.
The utility model discloses following beneficial effect has:
1. the utility model discloses an adjust the water content and the cooling rate of the mixed solution of different isopropyl alcohol-water, obtain different crystal forms, guaranteed the stability of technology.
2. And introducing nitrogen into the reaction kettle for protection, sequentially introducing methanol, CBZ-L-valine-acyclovir and a catalyst for reaction, transferring the filtrate to a crystallization kettle for crystallization, then introducing the filtrate into a second filtering device for filtering and washing, and introducing filter residues into a first dryer for drying to obtain a valacyclovir hydrochloride crude product. And (3) refining the valacyclovir hydrochloride crude product in a refining kettle, adjusting the water content in isopropanol, cooling and crystallizing in a first heat exchanger and a second heat exchanger, a third heat exchanger and a fourth heat exchanger, and drying in a second dryer under a vacuum environment to obtain products with different crystal forms.
3. The upper part of the first dryer is also communicated with a liquid nitrogen tank through a pipeline, and after the valacyclovir hydrochloride crude product is dried, nitrogen is filled for full dilution, so that the valacyclovir hydrochloride crude product is prevented from absorbing moisture and deteriorating in the storage process.
4. The first dryer is communicated with the first buffer tank and the first vacuum pump in sequence through a pipeline, and the second dryer is communicated with the second buffer tank and the second vacuum pump in sequence through a pipeline. Volatile alcohols in the drying process enter the first buffer tank and the second buffer tank to be absorbed and then discharged, so that the environmental pollution is reduced.
5. An isopropanol recovery pipe is arranged on the outer side of the gas-liquid separator and above the bottom of the return pipe. The gas phase isopropanol is separated at the upper part of the gas-liquid separator, so that the separation effect is improved.
Drawings
FIG. 1 is a schematic structural view of the present invention;
FIG. 2 is a schematic view of a gas-liquid separator;
in the figure: reaction kettle 1, first filtering device 2, crystallization kettle 3, propanol inlet pipe 301, second filtering device 4, first dryer 5, refining kettle 6, crystallization solvent inlet pipe 601, first heat exchanger 7, second heat exchanger 8, third heat exchanger 9, fourth heat exchanger 10, vacuum filter 11, nitrogen tank 12, methanol tank 13, CBZ-L-valine-acyclovir feed tank 14, catalyst preparation tank 15, formic acid tank 16, concentrated hydrochloric acid tank 17, condenser 18, gas-liquid separator 19, second return pipe 1901, isopropanol recovery pipe, second dryer 20, first buffer tank 21, first vacuum pump 22, liquid nitrogen tank 23, second buffer tank 24, second vacuum pump 25.
Detailed Description
Example 1
Referring to fig. 1-2, a device for producing valacyclovir hydrochloride in different crystal forms comprises a reaction kettle 1, the reaction kettle 1 is sequentially connected with a first filtering device 2, a crystallization kettle 3, a second filtering device 4, a first dryer 5 and a refining kettle 6 through pipelines, a discharge port at the bottom of the refining kettle 6 is respectively communicated with a first heat exchanger 7 and a second heat exchanger 8 through pipelines, the second heat exchanger 8 is sequentially communicated with a third heat exchanger 9 and a fourth heat exchanger 10 through pipelines, discharge ports of the first heat exchanger 7 and the fourth heat exchanger 10 are respectively communicated with a vacuum filter 11 through pipelines, the upper part of the refining kettle 6 forms a loop with a condenser 18 and a gas-liquid separator 19 in sequence, a pipeline at the bottom of the gas-liquid separator 19 is inserted below the liquid level in the refining kettle 6, a crystallization solvent inlet pipe 601 is arranged at a feed inlet of the refining kettle 6, and a filter residue discharge hole of the vacuum filter 11 is communicated with a feed inlet of the second dryer 20.
Preferably, the bottom of the reaction kettle 1 is provided with a nitrogen inlet pipe communicated with a nitrogen tank 12, a feeding port above the reaction kettle 1 is respectively communicated with a methanol tank 13, a CBZ-L-valine-acyclovir raw material tank 14, a catalyst preparation tank 15, a formic acid tank 16 and a concentrated hydrochloric acid tank 17, and a feeding port of the catalyst preparation tank 15 is communicated with the methanol tank 13.
Preferably, the crystallization vessel 3 is provided with a propanol inlet pipe 301.
Preferably, the upper part of the first dryer 5 is communicated with a first buffer tank 21 and a first vacuum pump 22 in sequence through pipelines.
Further preferably, the upper part of the first dryer 5 is also communicated with a liquid nitrogen tank 23 through a pipeline.
Preferably, the second dryer 20 is connected to a second buffer tank 24 and a second vacuum pump 25 through pipes.
Preferably, the return pipe 1901 of the condenser 18 communicating with the gas-liquid separator 19 is inserted into the gas-liquid separator 19, and an isopropyl alcohol recovery pipe 1902 is provided outside the gas-liquid separator 19 above the bottom of the return pipe 1901.
The working principle of the device is as follows: introducing nitrogen into a reaction kettle 1 and a nitrogen tank 12 for protection, and sequentially introducing 39.0g of methanol and 10.0g of CBZ-L-valine-acyclovir into the reaction kettle 1, wherein the weight ratio of the methanol to the CBZ-L-valine-acyclovir is 35-45: 10; adding palladium carbon into a catalyst preparation tank 15, introducing pure water and methanol (the weight ratio of the palladium carbon to the purified water to the methanol is (0.8-1.5): (3.5-4.5): 1), uniformly stirring, then adding into a reaction kettle 1, heating to 15-25 ℃, adding formic acid (the addition of the formic acid is 15% -20% of the weight of the CBZ-L-valine-acyclovir), and continuously heating to 35-45 ℃ for reaction for 1.5-2.5 h. Then adding hydrochloric acid and methanol solution (wherein the mass ratio of concentrated hydrochloric acid to alcohol is 1: 10-14), adjusting the pH value to 3.5-4.5, controlling the temperature to 35-45 ℃, stirring, cooling to 15-25 ℃, stirring for 8-12h, entering a first filtering device 2, filtering, transferring filtrate to a crystallization kettle 3, adding 117.5g of acetone into a propanol inlet pipe 301, wherein the acetone is 120 times of 110-fold organic acid of the mass of CBZ-L-valine-acyclovir, cooling to 8-12 ℃, stirring, crystallizing for 3.5-4.5h, entering a second filtering device 4, filtering and washing, and drying filter residues in a first dryer 5 to obtain a valacyclovir hydrochloride crude product.
The valacyclovir hydrochloride crude product at the discharge port of the first dryer 5 enters a refining kettle 6 for refining, mixed solution of isopropanol and water in a volume ratio of 6:1 is introduced, the refining kettle 6 is heated to 80-90 ℃, condensation reflux is carried out for 1.2-2h, and then liquid in the refining kettle 6 enters a first heat exchanger 7 and a second heat exchanger 8 for cooling crystallization to form different crystal forms according to the requirements of the different crystal forms. The temperature of the inner part of the first heat exchanger 7 is 0 ℃, and the cooling temperatures of the second heat exchanger 8, the third heat exchanger 9 and the fourth heat exchanger 10 are 60-80 ℃, 45-65 ℃ and 25-40 ℃ respectively. Nucleation crystallization is carried out, the crystal enters a vacuum filter 11 to be filtered to obtain filter residue, and then the filter residue enters a second dryer 20 to be dried under the vacuum environment to obtain products with different crystal forms. Wherein, when the water content in the mixed solution of isopropanol and water is less than 5 percent after condensation and reflux, the mixed solution enters a second heat exchanger 8, a third heat exchanger 9 and a fourth heat exchanger 10 to be sequentially cooled and crystallized to obtain a crystal form VII with characteristic diffraction peaks of 8.6 degrees, 10.8 degrees, 14.5 degrees, 16.4 degrees, 18.1 degrees, 20.0 degrees, 23.9 degrees, 26.2 degrees +/-0.2 degrees; condensing and refluxing until the water content in the mixed solution of isopropanol and water is 5.5-8%, directly cooling the mixed solution to 0 ℃ in a first heat exchanger 7 to crystallize to obtain a crystal form II with characteristic diffraction peaks of 6.6 degrees, 9.2 degrees, 15.6 degrees, 19.0 degrees, 26.3 degrees and 27.4 degrees +/-0.2 degrees, or sequentially cooling and crystallizing the mixed solution in a second heat exchanger 8, a third heat exchanger 9 and a fourth heat exchanger 10 to obtain a crystal form V with characteristic diffraction peaks of 3.6 degrees, 9.4 degrees, 10.8 degrees, 12.1 degrees, 13.3 degrees, 14.5 degrees, 16.4 degrees and 23.7 degrees +/-0.2 degrees; condensing and refluxing until the water content in the mixed solution of isopropanol and water is more than 9%, sequentially entering a second heat exchanger 8, a third heat exchanger 9 and a fourth heat exchanger 10 for cooling and crystallizing to obtain a crystal form I with characteristic diffraction peaks of 3.7 degrees, 8.6 degrees, 9.5 degrees, 10.6 degrees, 10.9 degrees, 16.5 degrees, 20.1 degrees, 24.0 degrees +/-0.2 degrees.
In addition, it should be noted that the specific embodiments described in the present specification may be different in the components, the shapes of the components, the names of the components, and the like, and the above description is only an example of the structure of the present invention. All the equivalent changes or simple changes made according to the structure, characteristics and principle of the utility model are included in the protection scope of the utility model. Various modifications, additions and substitutions may be made by those skilled in the art without departing from the scope of the invention as defined in the accompanying claims.
Claims (7)
1. The utility model provides a production facility of different crystal forms of valaciclovir hydrochloride, includes reation kettle (1), its characterized in that: the reaction kettle (1) is sequentially connected with a first filtering device (2), a crystallization kettle (3), a second filtering device (4), a first dryer (5) and a refining kettle (6) through pipelines, a discharge hole at the bottom of the refining kettle (6) is respectively communicated with a first heat exchanger (7) and a second heat exchanger (8) through pipelines, the second heat exchanger (8) is sequentially communicated with a third heat exchanger (9) and a fourth heat exchanger (10) through pipelines, discharge holes of the first heat exchanger (7) and the fourth heat exchanger (10) are respectively communicated with a vacuum filter (11) through pipelines, a loop is formed above the refining kettle (6) and is sequentially connected with a condenser (18) and a gas-liquid separator (19), a pipeline at the bottom of the gas-liquid separator (19) is inserted below the liquid level in the refining kettle (6), a crystallization solvent inlet pipe (601) is arranged at a feed inlet of the refining kettle (6), and a filter residue discharge hole of the vacuum filter (11) is communicated with a feed inlet of the second dryer (20).
2. The apparatus of claim 1, wherein: the bottom of the reaction kettle (1) is provided with a nitrogen inlet pipe communicated with a nitrogen tank (12), a feeding port above the reaction kettle (1) is respectively communicated with a methanol tank (13), a CBZ-L-valine-acyclovir raw material tank (14), a catalyst preparation tank (15), a formic acid tank (16) and a hydrochloric acid tank (17), and a feeding port of the catalyst preparation tank (15) is communicated with the methanol tank (13).
3. The apparatus of claim 1, wherein: and the crystallization kettle (3) is provided with a propanol inlet pipe (301).
4. The apparatus of claim 1, wherein: the upper part of the first dryer (5) is communicated with a first buffer tank (21) and a first vacuum pump (22) in sequence through pipelines.
5. The apparatus of claim 4, wherein: the upper part of the first dryer (5) is also communicated with a liquid nitrogen tank (23) through a pipeline.
6. The apparatus of claim 1, wherein: the upper part of the second dryer (20) is communicated with a second buffer tank (24) and a second vacuum pump (25) in sequence through pipelines.
7. The apparatus of claim 1, wherein: a return pipe (1901) of the condenser (18) communicated with the gas-liquid separator (19) is inserted into the gas-liquid separator (19), and an isopropanol recovery pipe (1902) is arranged on the outer side of the gas-liquid separator (19) and above the bottom of the return pipe (1901).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516945A (en) * | 2020-11-27 | 2021-03-19 | 江苏嘉逸医药有限公司 | Device and method for purifying parecoxib sodium |
| CN113976069A (en) * | 2021-10-28 | 2022-01-28 | 重庆医药高等专科学校 | Production system of cefquinome sulfate intermediate 7-amino cefquinome |
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2019
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516945A (en) * | 2020-11-27 | 2021-03-19 | 江苏嘉逸医药有限公司 | Device and method for purifying parecoxib sodium |
| CN112516945B (en) * | 2020-11-27 | 2022-05-20 | 江苏嘉逸医药有限公司 | Device and method for purifying parecoxib sodium |
| CN113976069A (en) * | 2021-10-28 | 2022-01-28 | 重庆医药高等专科学校 | Production system of cefquinome sulfate intermediate 7-amino cefquinome |
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