CN218459521U

CN218459521U - Equipment for synthesizing bulk drug vonoprazan fumarate

Info

Publication number: CN218459521U
Application number: CN202222843625.7U
Authority: CN
Inventors: 杨海洋
Original assignee: Wudi Rongchuan Chemical Technology Co ltd
Current assignee: Wudi Rongchuan Chemical Technology Co ltd
Priority date: 2022-10-27
Filing date: 2022-10-27
Publication date: 2023-02-10
Anticipated expiration: 2032-10-27

Abstract

The utility model discloses bulk drug vonoprazan fumarate synthesis equipment, which comprises a reaction kettle arranged at the front end; the upper part of the reaction kettle is connected with a first elevated tank through a pipeline; a discharge port of the reaction kettle is connected with a first rotary groove and a second rotary groove in parallel through a pipeline; the reaction kettle is connected with a first storage tank through a pipeline; the rear end of the reaction kettle is connected with a concentration kettle through a pipeline; the concentration kettle is sequentially connected with a first condenser and a second storage tank through pipelines; the outlet of the concentration kettle is connected with a crystallization kettle through a pipeline; the upper part of the crystallization kettle is connected with a second elevated tank through a pipeline; the discharge port of the crystallization kettle is connected with a centrifuge. Through the optimization and the adjustment of the special equipment facility flow, the effects of reducing the production cost and improving the production efficiency are achieved, so that the production system is more reasonable in arrangement and high in production efficiency.

Description

Equipment for synthesizing bulk drug vonoprazan fumarate

Technical Field

The utility model belongs to bulk drug production facility field, concretely relates to bulk drug fumaric acid vonoprazan synthesizer.

Background

Vonoprazan fumarate (vonoprazan fumarate, TAK-438,1), chemical name 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -3-methylaminomethyl-1H-pyrrole fumarate, is a potassium ion competitive acid retarding drug (P-CAB) developed by Wutian pharmaceutical (Takeda) of Japan, and is first marketed in Japan 12 months 2014, and belongs to a relatively novel gastric drug. Has good curative effect on gastric acid related diseases such as erosive esophagitis, helicobacter pylori infection, duodenal ulcer and gastric ulcer clinically, and has relatively high tolerance and safety.

The development and production of Vonoprazan fumarate are beneficial to forming the production of various stomach medicaments, increasing the product varieties, and meeting the requirements of patients with different levels and different indications besides economic benefits. At present, the existing equipment for synthesizing the vonoprazan fumarate product cannot achieve ideal yield; the production process of the special equipment achieves the aims of reducing the production cost and improving the production efficiency by optimizing and adjusting the process of the special equipment facility.

SUMMERY OF THE UTILITY MODEL

The utility model provides a former of bulk drug fumaric acid vonoprazan equipment for synthesizing, prior art's shortcoming can be solved in the use of this equipment, and production system arranges more rationally, and production efficiency is high.

In order to achieve the above purpose, the utility model provides a following technical scheme: a raw material medicine Vonoprazan fumarate synthesis device comprises a reaction kettle arranged at the front end; the upper part of the reaction kettle is connected with a first elevated tank through a pipeline; a discharge port of the reaction kettle is connected with a first rotary groove and a second rotary groove in parallel through a pipeline; the reaction kettle is connected with a first storage tank through a pipeline; the rear end of the reaction kettle is connected with a concentration kettle through a pipeline; the concentration kettle is sequentially connected with a first condenser and a second storage tank through pipelines; the outlet of the concentration kettle is connected with a crystallization kettle through a pipeline; the upper part of the crystallization kettle is connected with a second elevated tank through a pipeline; the discharge port of the crystallization kettle is connected with a centrifuge.

Preferably, the reaction kettle is connected with a second condenser through a pipeline.

Preferably, a first visual cup is arranged on a pipeline between the reaction kettle and the first elevated tank.

Preferably, a third condenser is arranged on the crystallization kettle through a pipeline.

Preferably, a second visual cup is arranged on a pipeline between the crystallization kettle and the second elevated tank.

Preferably, the rear end of the centrifuge is connected with a ground groove through a pipeline.

Compared with the prior art, the beneficial effects of the utility model are that: through the optimization and the adjustment of the special equipment facility flow, the effects of reducing the production cost and improving the production efficiency are achieved, so that the production system is more reasonable in arrangement and high in production efficiency.

Other features of the present disclosure and advantages thereof will become apparent from the following detailed description of exemplary embodiments thereof, which proceeds with reference to the accompanying drawings.

Drawings

In order to more clearly illustrate the embodiments of the present disclosure or technical solutions in related arts, the drawings used in the description of the embodiments or related arts will be briefly introduced below, it is obvious that the drawings in the following description are only embodiments of the present disclosure, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is an overall view of the synthesis apparatus of the present invention;

in the figure: 1. the system comprises a reaction kettle, 2, a first elevated tank, 3, a first turnover tank, 4, a second turnover tank, 5, a first storage tank, 6, a concentration kettle, 7, a first condenser, 8, a second storage tank, 9, a crystallization kettle, 10, a second elevated tank, 11, a centrifugal machine, 12, a second condenser, 13, a first visual cup, 14, a third condenser, 15, a second visual cup, 16 and a ground tank.

Detailed Description

The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. Based on the embodiments in the present invention, all other embodiments obtained by a person skilled in the art without creative efforts belong to the protection scope of the present invention.

Unless specifically stated otherwise, the relative arrangement of the components and steps, the numerical expressions, and numerical values set forth in these embodiments do not limit the scope of the present invention. Meanwhile, it should be understood that the sizes of the respective portions shown in the drawings are not drawn in an actual proportional relationship for the convenience of description. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate. In all examples shown and discussed herein, any particular value should be construed as merely illustrative, and not limiting. Thus, other examples of the exemplary embodiments may have different values. It should be noted that: like reference numbers and letters refer to like items in the following figures, and thus, once an item is defined in one figure, further discussion thereof is not required in subsequent figures.

For ease of description, spatially relative terms such as "above … …", "above … …", "above … … upper surface", "above", etc. may be used herein to describe the spatial positional relationship of one device or feature to other devices or features as shown in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is turned over, devices described as "above" or "on" other devices or configurations would then be oriented "below" or "under" the other devices or configurations. Thus, the exemplary term "above … …" may include both orientations of "above … …" and "below … …". The device may be otherwise variously oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

Referring to fig. 1, the present invention provides a technical solution: a bulk drug Vonoprazan fumarate synthesis device comprises a reaction kettle 1 arranged at the front end; the upper part of the reaction kettle 1 is connected with a first elevated tank 2 through a pipeline; a discharge port of the reaction kettle 1 is connected in parallel with a first rotary groove 3 and a second rotary groove 4 through pipelines; the reaction kettle 1 is connected with a first storage tank 5 through a pipeline; the rear end of the reaction kettle 1 is connected with a concentration kettle 6 through a pipeline; the concentration kettle 6 is sequentially connected with a first condenser 7 and a second storage tank 8 through pipelines; the outlet of the concentration kettle 6 is connected with a crystallization kettle 9 through a pipeline; the upper part of the crystallization kettle 9 is connected with a second elevated tank 10 through a pipeline; the discharge port of the crystallization kettle 9 is connected with a centrifuge 11. The reaction kettle 1 is connected with a second condenser 12 through a pipeline. A first visual cup 13 is arranged on the pipeline between the reaction kettle 1 and the first elevated tank 2. The crystallization kettle 9 is provided with a third condenser 14 through a pipeline. A second visual cup 15 is arranged on the pipeline between the crystallization kettle 9 and the second elevated tank 10. The rear end of the centrifuge 11 is connected with a ground groove 16 through a pipeline.

The implementation process of the equipment comprises the following steps:

a certain amount of methanol is added into the reaction kettle 1, stirring is started after the reaction is finished, and a specified amount of methylamine methanol solution with the concentration of 30 percent of reactants is added. After the feeding is finished, adjusting the temperature to 20-30 ℃, and controlling the temperature to react for 0.5-1 hour. After that, a jacket freezing brine inlet-outlet valve of the reaction kettle 1 is opened, the temperature is reduced to-15 to-10 ℃, a 100L dripping valve of the first elevated tank 2 is opened, and the prepared N, N-dimethylacetamide solution of sodium borohydride is dripped at the temperature of-15 to-5 ℃. After the dropwise addition, the temperature is controlled to be between 15 ℃ below zero and 5 ℃ below zero, the reaction is started to be sampled and monitored for 4 hours, and the sampling is carried out once every 1 hour until the reaction is monitored completely.

Quenching reaction: after the reaction is finished, a dropping valve of the first elevated tank 2 of 100L is opened, and hydrochloric acid is dropped to adjust the pH value of the system to 5-6 at the temperature of less than or equal to 10 ℃. After the dropwise addition, the temperature of the system is adjusted to 5-15 ℃, and the temperature is controlled to 5-15 ℃ to be stirred and react for 0.5-1 hour. After the reaction is finished, a certain amount of process water is added into the reaction kettle 1, ammonia water is added to adjust the pH value to 8-9, and the temperature is controlled to be 5-15 ℃ after the reaction is finished, and the reaction is stirred for 0.5 hour.

And adding a certain amount of ethyl acetate into the reaction kettle 1, stirring for about 20 minutes after the addition is finished, standing for about 40 minutes, separating, feeding the lower-layer water layer into the first transfer tank 3, and feeding the upper-layer organic layer into the second transfer tank 4. Pumping the water layer in the first transferring tank 3 into the reaction kettle 1, pumping quantitative ethyl acetate into the reaction kettle, stirring for about 20 minutes after the addition is finished, standing for about 40 minutes, separating, feeding the lower water layer into the first transferring tank 3, and feeding the upper organic layer into the second transferring tank 4. Pumping the water layer in the first circulation tank 3 into the reaction kettle 1, pumping quantitative ethyl acetate into the reaction kettle, stirring for about 20 minutes after the addition is finished, standing for about 40 minutes, separating liquid, allowing the lower water layer to be separated into the first circulation tank 3, and allowing the upper organic layer to remain in the reaction kettle 1.

Concentration and distillation: the stirring of the reaction kettle 1 is opened, a jacket steam inlet-outlet valve is opened, the temperature is increased, the pressure is reduced, the solvent is distilled into a first storage tank 5 of 200L, and the pressure is reduced and the distillation is carried out when the temperature is controlled to be 30-40 ℃. After partial solvent is distilled under reduced pressure, the bottom valve of the reaction kettle 1 is opened, the feed valve of the concentration kettle 6 is opened, and the feed liquid is transferred to the concentration kettle 6. Opening the stirring of the concentration kettle 6, opening a jacket steam inlet and outlet valve, heating and distilling the solvent under reduced pressure to a second storage tank 8 of 200L, controlling the temperature to be 30-40 ℃, controlling the vacuum degree to be less than or equal to-0.08 MPa, distilling under reduced pressure until no obvious liquid drops are evaporated.

And (3) crystallization separation: quantitative ethyl acetate and N, N-dimethylacetamide are pumped into the concentration kettle 6, stirring is started, and stirring is carried out until the concentrate is dissolved. After finishing the process, the bottom valve of the concentration kettle 6 is opened, and the feeding valve of the crystallization kettle 9 is opened to transfer the material to the crystallization kettle 9. Opening the crystallization kettle 9 and stirring, and adjusting the temperature of the feed liquid to 20-30 ℃. After the completion of the operation, the second elevated tank 10 is opened, and the dropping valve is opened to control the temperature to be 20-30 ℃, and then a quantitative N, N-dimethylacetamide solution of fumaric acid is dropped. After the dripping is finished, controlling the temperature to be 20-30 ℃, stirring and crystallizing for 7-8 hours. And (3) paving filter cloth in a centrifuge (11), opening a bottom valve of a crystallization kettle (9) after crystallization is finished, and putting the feed liquid into the centrifuge (11) for centrifugation until a liquid outlet of the centrifuge (11) basically has no liquid drops. After that, the solution was rinsed with a fixed amount of ethyl acetate. And after the centrifugation is finished, putting the wet product into a turnover barrel, and drying the wet product. The spent centrifuge effluent enters the sump 16.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A bulk drug vonoprazan fumarate synthesis device is characterized in that: the synthesis equipment comprises a reaction kettle (1) arranged at the front end; the upper part of the reaction kettle (1) is connected with a first elevated tank (2) through a pipeline; a discharge port of the reaction kettle (1) is connected with a first rotary groove (3) and a second rotary groove (4) in parallel through a pipeline; the reaction kettle (1) is connected with a first storage tank (5) through a pipeline; the rear end of the reaction kettle (1) is connected with a concentration kettle (6) through a pipeline; the concentration kettle (6) is sequentially connected with a first condenser (7) and a second storage tank (8) through pipelines; the outlet of the concentration kettle (6) is connected with a crystallization kettle (9) through a pipeline; the upper part of the crystallization kettle (9) is connected with a second elevated tank (10) through a pipeline; and a discharge hole of the crystallization kettle (9) is connected with a centrifugal machine (11).

2. The bulk drug vonoprazan fumarate synthesis apparatus according to claim 1, wherein: the reaction kettle (1) is connected with a second condenser (12) through a pipeline.

3. The bulk drug vonoprazan fumarate synthesis apparatus of claim 1, wherein: a first visual cup (13) is arranged on a pipeline between the reaction kettle (1) and the first elevated tank (2).

4. The bulk drug vonoprazan fumarate synthesis apparatus of claim 1, wherein: and a third condenser (14) is arranged on the crystallization kettle (9) through a pipeline.

5. The bulk drug vonoprazan fumarate synthesis apparatus of claim 1, wherein: a second visual cup (15) is arranged on a pipeline between the crystallization kettle (9) and the second elevated tank (10).

6. The bulk drug vonoprazan fumarate synthesis apparatus of claim 1, wherein: the rear end of the centrifugal machine (11) is connected with a ground groove (16) through a pipeline.