CN112176009A

CN112176009A - Method for continuously preparing 3-phthalimido propionaldehyde in batches by utilizing microreactor

Info

Publication number: CN112176009A
Application number: CN202011059835.6A
Authority: CN
Inventors: 陈剑戈; 张喜通
Original assignee: Jiangsu Jiming Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Jiming Pharmaceutical Technology Co ltd
Priority date: 2020-09-30
Filing date: 2020-09-30
Publication date: 2021-01-05

Abstract

The invention belongs to the technical field of preparation of 3-phthalimide propionaldehyde, and particularly relates to a method for continuously preparing 3-phthalimide propionaldehyde in batches by using a microreactor. The method comprises the following steps: pumping the phthalimide solution, the phosphate buffer solution containing the pork liver lipase and the acrolein into the microreactor through a flow controller respectively for mixing reaction, then enabling the mixed reaction liquid to enter a product collecting tank, concentrating to remove the organic solvent in the product collecting tank, filtering and drying to obtain the target product. By utilizing the method provided by the invention, the two-phase reaction medium is more fully mixed, and the reaction efficiency is greatly improved.

Description

Method for continuously preparing 3-phthalimido propionaldehyde in batches by utilizing microreactor

Technical Field

The invention belongs to the technical field of preparation of 3-phthalimide propionaldehyde, and particularly relates to a method for continuously preparing 3-phthalimide propionaldehyde in batches by using a microreactor.

Background

Atorvastatin (lipitor) has broken through $ 1500 billion for its global cumulative sales as a bright star product of pfeiri. Although lipitor has passed the patent protection period, lipitor still has considerable market prospect as a heavy lipid-lowering drug in the primary research and the imitation drugs of cardiovascular drugs. According to statistics, with the accelerated aging of China, the market scale of the domestic atorvastatin calcium tablets reaches 160 hundred million yuan. The 3-phthalimidopropional is a key intermediate of atorvastatin (lipitor) which is a lipid-lowering drug, and the structural formula of the intermediate is shown as follows:

there are many synthetic documents on 3-phthalimidopropional, and the following 5 types are summarized:

1) the potassium phthalimide salt is reacted with dibromide, and the obtained intermediate is oxidized to obtain the product (JACS, 1988, 5579-. The method needs two steps, and the second step needs deep cooling (below minus 50 ℃), needs a special deep cooling kettle, and has high reaction requirement and high reaction energy consumption.

2) N-vinyl phthalimide is reacted with carbon monoxide under the catalysis of rhodium, a noble metal (chemistry. A European Journal,2012, 9992-. The process needs noble metal rhodium and a more noble raw material of N-vinyl phthalimide, and has high production cost. Carbon monoxide is needed in the reaction process, and the danger is high. In addition, the yield is only 40 percent, and the method is not beneficial to large-scale industrial production.

3) Is prepared by oxidizing N-allyl phthalimide. The process needs to use a noble metal palladium catalyst and silver nitrate, and the cost of the raw materials is high. In addition, a pressure device is required to completely react the raw material with oxygen (Angew Chem, 2013, 11467-11470), and the reaction conditions are relatively harsh.

4) Phthalic anhydride is reacted with 3-hydroxy propylamine, and oxidation is carried out after the reaction. The process requires two steps of reaction and the second oxidation requires a cryogenic reactor (Swern oxidation) or an expensive oxidant (Dess-Martin oxidation).

5) The target product is prepared by one-step method by taking phthalimide and acrolein as raw materials. The raw materials of the process are all relatively cheap. However, in the reaction process of the process, the catalyst can further catalyze the dimerization of the product, so that dimeric impurities (1% -2%) which are difficult to remove are generated, and the purity of the product is poor (92% -93%). The purity requirement of key intermediates in actual production cannot be met.

The company compares the advantages and the disadvantages of the existing process, obtains a method for synthesizing 3-phthalimide propionaldehyde by biological enzyme catalysis through innovation, improvement and optimization, and applies for a patent (CN 105483174A). By adopting the process in the patent, the target product with the purity of more than 99.0 percent can be obtained with the yield of more than 92 percent.

Through production verification of several years, the process is found to have better stability, but some problems are also exposed, and the main problems are as follows: 1) two-phase reaction, the reaction time is long (each batch of reaction needs about 3 days), so the productivity is low; 2) the dosage of the enzyme catalyst is larger, and the cost still has a further reduced space; 3) acrolein is easy to generate dimerization or high polymer, so that the purity of the product is reduced; when multiple batches of production are carried out repeatedly, a small amount of high polymer is found to be adhered to the device after every 2-3 batches of production, and the reaction kettle needs to be cleaned (2-3 days are needed for each cleaning), so that the method becomes an important factor for restricting the improvement of the production efficiency; 4) since acrolein cannot be completely reacted, residual acrolein has bad smell and extremely high toxicity, so that the cleaning work is very complicated, and great inconvenience is brought to production.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, including the problems in the production of the prior art (batch reaction kettle) of our patent, and aims to provide a method for continuously preparing 3-phthalimide propionaldehyde in batches by utilizing a microreactor, which is safer in operation, more suitable for multi-batch continuous production and simple in operation.

In order to achieve the above purpose, the invention provides the following technical scheme:

a method for continuously preparing 3-phthalimido propionaldehyde in batches by utilizing a microreactor has the following reaction formula:

the method comprises the following steps:

pumping the phthalimide solution, the phosphate buffer solution containing the pork liver lipase and the acrolein into the microreactor through a flow controller respectively for mixing reaction, then enabling the mixed reaction liquid to enter a product collecting tank, concentrating to remove the organic solvent in the product collecting tank, filtering and drying to obtain a target product;

the micro-reactor comprises a plurality of micro-reactor modules arranged in parallel, wherein each micro-reactor module comprises a plurality of micro-reaction chambers and a micro-channel connected with the micro-reaction chambers, the micro-channel is a plurality of micro-channels which are arranged in parallel and form an S-shaped structure, the micro-reaction chambers are in a heart-shaped structure and are connected end to end with each other along the flowing direction of reaction liquid, the inlet ends of the micro-reaction chambers are large ends, and the outlet ends of the micro-reaction chambers are small ends.

In the invention, after each previous batch of target product is discharged from the microreactor, the feeding work of the next batch of reaction is directly carried out, and the microreactor is cleaned until the purity of the product is less than the required purity. The purity of the target product 3-phthalimidepropanal of the invention is required to be not less than 99%.

Preferably, the inner diameter of the microreactor is 0.05-5 mm.

Preferably, the total flow rate of the phthalimide solution, the phosphate buffer solution of porcine liver lipase and the acrolein into the single module of the microreactor is 1.0-30.0 mL/min.

Preferably, the solvent used in the phthalimide solution is one or more of acetone, ethanol, and acetonitrile.

Preferably, the phthalimide solution is prepared by mixing the phthalimide with the solvent in a weight ratio of 0.5 to 3: 1.

Preferably, the phosphate buffer solution is a sodium phosphate or potassium phosphate buffer.

Further preferably, the sodium phosphate buffer solution is composed of Na₂HPO₄And/or NaH₂PO₄Is prepared by the following steps.

Further preferably, the potassium phosphate buffer consists of K₂HPO₄And/or KH₂PO₄Is prepared by the following steps.

Preferably, the pig liver lipase is added in an amount of 0.02 to 0.5 times the weight of phthalimide.

Preferably, the weight ratio of acrolein to phthalimide is between 0.35 and 3.0: 1.

preferably, the microreactor reaction temperature is from 30 to 50 ℃.

Preferably, the microreactor consists of 60 microreactor modules arranged side by side.

Compared with the prior art, the invention has the following beneficial effects:

(1) by utilizing the method provided by the invention, two-phase reaction media are more fully mixed, the polymerization risk of acrolein is reduced, a reaction device does not need to be cleaned regularly, the method is suitable for multi-batch continuous production, and the production efficiency is greatly improved.

(2) By adopting the microreactor reaction condition provided by the invention, the time of the pig liver lipase in a reaction system and a two-phase medium is short, and the enzyme inactivation ratio is reduced, so that the enzyme dosage is reduced, and the cost is reduced.

(3) Experiments show that the microreactor can be continuously used for 3-4 months without cleaning the reactor by adopting the reaction conditions of the microreactor. Compared with the condition that the traditional reaction kettle needs to be cleaned once every 2-3 batches (about 3 days per batch), the method has the advantages that the production efficiency is 2 times that of the traditional reaction kettle by using 3 days per batch of reaction, 3 days are required for cleaning once every 3 batches, and 30 days are calculated every month.

Drawings

FIG. 1 is a schematic diagram of a reaction scheme provided by the present invention;

FIG. 2 is a schematic view of a microreactor module structure;

FIG. 3 is a schematic diagram of a microreactor in a microreactor;

FIG. 4 is a schematic diagram of a parallel arrangement of microreactor modules.

Detailed Description

The method of the present invention is described below with reference to specific examples to make it easier to understand and understand the technical solution of the present invention, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1

As shown in fig. 1: 207.0g of phthalimide was dissolved in 100mL of acetone and placed in a 500mL glass bottle (stock A). In a 2L three-necked flask, Na was placed₂HPO₄And Na₂HPO₄To the buffer solution (pH 7.5, 1500mL), while stirring and controlling the temperature at 30 ℃, 31.1g of pig liver esterase was added (stock tank B). 106.2g of acrolein was put in a 250mL glass bottle (tank C) and the temperature was kept at 20 ℃. And (3) controlling the flow rate of the materials in the three storage tanks by the flow controllers respectively to enable the flow rate ratio of the three storage tanks to correspond to the corresponding volume ratio, and pumping the three materials into the microreactor (single module). The total flow rate was controlled to be 3.0 mL/min. The temperature of the microreactor is controlled to be 45 ℃. And the reaction liquid flowing through the microreactor enters a product collecting tank. The organic solvent in the collection tank was concentrated off and then filtered and the filter cake was dried to yield 268.4g, 94% yield and 99.6% purity.

In this embodiment, as shown in fig. 2 to 4, the microreactor comprises 60 microreactor modules arranged in parallel, wherein each microreactor module comprises 51 microreactor chambers 1 and microchannels 2 connecting the microreactor chambers, the microchannels 2 are folded into 7 microchannels arranged in parallel and forming an S-shaped structure, the microreactor chambers 1 are in a "heart" shape and are connected end to end along the flowing direction of the reaction liquid, the inlet end of each microreactor chamber 1 is a large end, and the outlet end of each microreactor chamber is a small end. As shown in the internal structure of the micro-reaction chamber in FIG. 3, the cavities formed between the

channels

11, 12, 13 of the micro-reaction channels constitute channels for the flow of the reaction solution. Wherein 11 is similar to the baffle plate function, so that the reaction solution forms obvious mixing effect; 12 is the effect of increasing the mixing effect of the system.

The inner diameter of the microreactor in this example was 2 mm.

The total time per batch of this example was about 20 hours.

Repeat the above experiment 6 batches in the above reaction flask (without washing the flask, directly feed the next batch reaction) and record the product purity and yield of each batch as follows:

	batch 2	Batch 3	Batch 4	Batch 5	Batch 6
						Yield%	95％	94％	96％	97％	95％
Purity%	99.6％	99.7％	99.5％	99.6％	99.5％

Moreover, the yield and purity of the reaction product basically have no obvious decline trend along with the increase of the reaction batch.

Comparative example 1

Phthalimide (207g) and acrolein (106.2g) were charged into a reaction flask, followed by addition of acetone (100mL) and stirringAnd (4) dissolving. Then Na is added₂HPO₄And Na₂HPO₄The reaction temperature was controlled at 30 ℃ to give a buffer solution (pH 8.0, 1500mL), and pork liver lipase (100g) was added thereto and the reaction was stirred for 3 days. The acetone was removed by concentration under reduced pressure and filtered to give 3-phthalimide (27.3g) in 95% yield and 99.6% purity.

	batch 2	Batch 3	Batch 4	Batch 5	Batch 6
						Yield%	95％	94％	96％	95％	94％
Purity%	99.3％	99.0％	98.6％	98.1％	97.6％

Moreover, as the reaction batch increases, the yield of the reaction product does not decrease significantly, but the reaction purity decreases at a rate of about 0.5%.

When the reaction was carried out by the method of comparative example 1, the purity of the product was less than 99% from batch 4, because the reaction flask was not cleaned, and the purity requirement could not be satisfied.

In order to examine the effect of washing on the above reaction process, the inventors of the present application washed the reaction flask after the end of batch 3 and then performed batch 4, and the purity of the product obtained from batches 4, 5 and 6 was 99.4%, 99.3% and 99.1%, respectively. The yield has no obvious reduction trend. However, in batch 7, the purity of the product was only 98.7%, so the reaction flask had to be cleaned after batch 6.

Example 2

As shown in fig. 1: 207.0g of phthalimide were dissolved in 250mL of ethanol and placed in a 500mL glass bottle (stock A). In a 1L three-necked flask, K was placed₂HPO₄And K₂HPO₄The buffer solution (pH: 7.0,1200mL) was stirred and 16.6g of pig liver esterase was added thereto at 30 ℃. Then 118.0g acrolein was put into a 250mL glass bottle (tank C) and the temperature was kept within 20 ℃. And (3) controlling the flow rate of the materials in the three storage tanks by the flow controllers respectively to enable the flow rate ratio of the three storage tanks to correspond to the corresponding volume ratio, and pumping the three materials into the microreactor (single module). The total flow rate was controlled to be 10 mL/min. The temperature of the microreactor is controlled to be 45 ℃. And the reaction liquid flowing through the microreactor enters a product collecting tank. The organic solvent in the collection tank was concentrated off, then filtered and the filter cake was dried to yield 272.1g, 96% yield, 99.5% purity.

In this example, the reaction solution of each batch stayed in the micro reaction channel for about 9 minutes, and the time required for pumping the reaction material into the micro reactor was about 3 hours and about 9 minutes in total.

Repeat the above experiment 6 batches in the above reaction flask (without washing the reaction flask, directly feed the next batch of reaction), record the product purity and yield of each batch of reaction,

the purity of the product in batch 6 was greater than 99.3% with no significant change in yield.

Example 3

As shown in fig. 1: 10.35Kg of phthalimide was dissolved in 12.5L of methanol and packed in a 25L plastic bucket (tank A). In a 100L glass reaction kettle, Na is arranged₂HPO₄And Na₂HPO₄The buffer solution (pH 7.5,50L) was stirred and 30 ℃ was controlled, and then 0.62Kg of pig liver esterase was added (stock tank B). Then 4.33Kg acrolein is put into a 10L glass bottle (storage tank C) and the storage temperature is less than 20 ℃. And (3) controlling the flow rate of the materials in the three storage tanks by the flow controllers respectively to enable the flow rate ratio of the three storage tanks to correspond to the corresponding volume ratio, and pumping the three materials into the microreactor (single module). The total flow rate was controlled to be 20.0 mL/min. The temperature of the microreactor is controlled to be 45 ℃. And the reaction liquid flowing through the microreactor enters a product collecting tank. The organic solvent in the collection tank was concentrated and removed, then filtered and the filter cake was dried to obtain 13.37Kg, 93% yield and 99.5% purity.

In this example, the reaction solution stayed in the micro reaction channel for about 5 minutes, and the time required for pumping the reaction material into the micro reactor was about 65 hours, and a total of 65 hours and 5 minutes was required.

the purity of the product in batch 6 was greater than 99.4% with no significant change in yield.

Example 4

As shown in fig. 1: 207.0g of phthalimide were dissolved in 250mL of methanol and placed in a 500mL glass bottle (stock A). In a 1L three-necked flask, Na was placed₂HPO₄And Na₂HPO₄The buffer solution (pH 8.0, 800mL) was stirred at 30 ℃ and 14.5g of pig liver esterase was added (stock tank B). Then 94.5g acrolein was put into a 250mL glass bottle (tank C) and keptThe storage temperature is within 20 ℃. And (3) controlling the flow rate of the materials in the three storage tanks by the flow controllers respectively to enable the flow rate ratio of the three storage tanks to correspond to the corresponding volume ratio, and pumping the three materials into the microreactor (single module). The total flow rate was controlled to be 1.5 mL/min. The temperature of the microreactor is controlled to be 40 ℃. And the reaction liquid flowing through the microreactor enters a product collecting tank. The organic solvent in the collection tank was concentrated off, then filtered and the filter cake was dried to yield 272.1g, 95% yield and 99.4% purity.

This example was repeated for 6 batches in succession, and then the microreactor was disassembled, and no dimeric stickies were found to be produced on the inner wall of the reactor. The 6 batches took about 90 hours. The product and purity of each batch were as follows:

batches of

1

2

3

4

5

6

Yield of

94％

95％

96％

93％

94％

Purity of

99.7％

99.3％

99.2％

99.4％

99.6％

99.5％

Example 5

As shown in fig. 1: 517.5Kg of phthalimide was dissolved in 725L of methanol in a 2000L reactor (stock tank A). In a 3000L reaction kettle, Na is prepared₂HPO₄And Na₂HPO₄The buffer solution (pH: 7.0,2500L) was stirred and 20.7Kg of pig liver esterase was added thereto at 30 ℃ to prepare a solution (stock tank B). Then 216Kg acrolein is put into a 500L enamel reactor (storage tank C) and the storage temperature is within 20 ℃. And (3) controlling the flow rate of the materials in the three reaction kettles by the flow controllers respectively to enable the flow rate ratio of the three reaction kettles to correspond to the corresponding volume ratio, and pumping the three materials into a reactor consisting of 60 microreactor modules. The total flow rate was controlled to be 1.2L/min (flow rate of 20mL/min for individual modules), and the time for which the reaction solution stayed in the micro reaction channel was about 5 min. The temperature of the microreactor is controlled to be 45 ℃. The reaction liquid after flowing through the microreactor enters a product collecting tank (a 5000L reaction kettle). The organic solvent in the reaction kettle is concentrated and removed, then the filtration is carried out, and the filter cake is dried to obtain 685Kg, the yield is 95 percent, and the purity is 99.4 percent.

In this example, the reaction solution stayed in the micro reaction channel for about 5 minutes, and the time required for pumping the reaction material into the micro reactor was about 55 hours, and a total of 55 hours and 5 minutes were required.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. The method for continuously preparing the 3-phthalimide propionaldehyde in batches by utilizing the microreactor has the following reaction formula:

the method comprises the following steps:

pumping the phthalimide solution, the phosphate buffer solution containing the pork liver lipase and the acrolein into the microreactor through a flow controller respectively for mixing reaction, then enabling the mixed reaction liquid to enter a product collecting tank, concentrating to remove the organic solvent in the product collecting tank, filtering and drying to obtain a target product; the micro-reactor comprises a plurality of micro-reactor modules arranged in parallel, wherein each micro-reactor module comprises a plurality of micro-reaction chambers and a micro-channel connected with the micro-reaction chambers, the micro-channel is a plurality of micro-channels which are arranged in parallel and form an S-shaped structure, the micro-reaction chambers are in a heart-shaped structure and are connected end to end with each other along the flowing direction of reaction liquid, the inlet ends of the micro-reaction chambers are large ends, and the outlet ends of the micro-reaction chambers are small ends.

2. The method for continuous batch production of 3-phthalimidopropional using a microreactor according to claim 1,

the solvent adopted in the phthalimide solution is one or more of acetone, ethanol and acetonitrile.

3. The method according to claim 1, wherein the phthalimide solution is prepared by mixing a solvent and phthalimide in a weight ratio of 0.5-3: 1.

4. The method for continuous batch production of 3-phthalimidopropional using a microreactor according to claim 1, wherein the phosphate buffer solution is a sodium phosphate or potassium phosphate buffer.

5. The method of claim 4 for continuous batch production of 3-phthalimidopropional using a microreactor, the sodium phosphate buffer solution being made of Na₂HPO₄And/or NaH₂PO₄Is prepared by the following steps.

6. The method for continuous batch production of 3-phthalimidopropional using a microreactor according to claim 1, wherein the amount of pig liver lipase added is 0.02 to 0.5 times the weight of phthalimide.

7. The method for continuous batch preparation of 3-phthalimidopropional using a microreactor according to claim 1, wherein the weight ratio of acrolein to phthalimide is 0.35-3.0: 1.

8. The method according to claim 1 for the continuous batch preparation of 3-phthalimidopropional using a microreactor having a microreactor reaction temperature of 30-50 ℃.

9. The method for continuous batch production of 3-phthalimidopropional using a microreactor as claimed in claim 1, wherein the total flow rate of the phthalimide solution, the phosphate buffer solution of porcine liver lipase and the acrolein into a single module of the microreactor is 1.0-30.0 mL/min.