Post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride

Abstract

The invention discloses a post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride, and belongs to the technical field of pharmacy, and the post-treatment process comprises the following steps: S1, continuous drying of a reaction solution: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction solution obtained by esterification reaction, and continuously pumping into a film evaporator to obtain a concentrated solution and a condensed solution; s2, pH adjustment: adjusting the pH with a weak base solution to obtain an adjusted dissolving solution, S3, resin decoloration: collecting a D-p-hydroxyphenylglycine methyl ester hydrochloride decoloration solution; s4, recycling: carrying out top washing on the resin column by using drinking water for a process, merging top washing water into the decoloring solution, and uniformly mixing to obtain a D-p-hydroxyphenylglycine methyl ester hydrochloride treatment solution, thereby finishing the treatment; the continuous feeding drying of the film evaporator is adopted to replace an in-tank decompression drying device in the prior art, so that the drying is quick; the traditional activated carbon decoloration is replaced by the resin decoloration, and the resin can be repeatedly recycled, so that the production cost is effectively reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride. Background Art

[0002] D-p-hydroxyphenylglycine methyl ester hydrochloride is an important intermediate for the synthesis of β-lactam antibiotics and is widely used in the enzymatic synthesis of amoxicillin. Since the enzymatic production of amoxicillin has great advantages over other methods in terms of environmental protection and energy consumption, the production of amoxicillin has been dominated by enzymatic synthesis in recent years, and the demand for D-p-hydroxyphenylglycine methyl ester hydrochloride has also increased rapidly. In view of this, there is also more demand for the post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride.

[0003] In the prior art, the post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride is mainly based on general in-tank vacuum distillation and drying, which has a slow distillation speed and needs to be dissolved and decolorized with activated carbon after the distillation is completed, which has a long cycle, high energy consumption and a poor working environment. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a post-treatment process of D-p-hydroxyphenylglycine methyl ester hydrochloride, comprising the following steps: S1, continuous drying of the reaction liquid: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction, controlling the temperature of the thin film evaporator to 40-80°C, the vacuum degree ≤-0.080MPa, and the rotation speed to 100-200rpm, and continuously injecting the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid into the thin film evaporator to obtain a concentrated solution and a condensate; when the content of D-p-hydroxyphenylglycine methyl ester hydrochloride in the concentrated solution is 450-500mg / mL and the purity is ≥98%, the feeding is completed and the concentrated solution is collected; S2. Adjust pH: When the temperature of the concentrated solution drops below 45°C, use a weak alkaline solution to adjust the pH to 1.0-1.5 to obtain the adjusted dissolved solution. S3, resin decolorization: the adjusted dissolved liquid is passed through the resin column at a flow rate of 2-4BV / h, and the feeding is stopped when the total feeding amount is 10-15BV, and the decolorization is completed to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride decolorized liquid; if the flow rate is too low, the feeding efficiency is reduced, and if the flow rate is too high, the quality of the decolorized liquid is reduced, which is not conducive to the subsequent treatment; S4, recovery: use 0.5-1.5 times the volume of the resin drinking water to top wash the resin column at a flow rate of 1-2BV / h, and add the top wash water into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorizing solution, mix well, and obtain the D-p-hydroxyphenylglycine methyl ester hydrochloride treated solution, and the treatment is completed.

[0005] Furthermore, in the step S1, the temperature of the thin film evaporator is controlled to be 60°C.

[0006] Furthermore, in step S2, when the temperature of the concentrated solution drops to 15-20°C, the pH value is adjusted to 1.2 with a weak alkaline solution to obtain an adjusted dissolved solution.

[0007] Moreover, in step S3, the weak alkaline solution is aqueous ammonia.

[0008] Furthermore, in the step S3, the resin is decolorized: the adjusted dissolved solution is passed through the resin column at a flow rate of 3 BV / h, and the passing is stopped when the total passing amount reaches 12 BV; Furthermore, in step S4, the resin column is top washed with process drinking water having a resin volume of 1 BV at a flow rate of 1 BV / h.

[0009] Moreover, after step S4 is completed, methanol with a volume of 1-2 times the resin volume is used to pass through the resin column at a flow rate of 1-2BV / h for alcohol analysis, and then 1-2 times the resin volume of 1 mol / L sodium hydroxide solution is used for alkali analysis at a flow rate of 1-2BV / h.

[0010] After step S4, 2 BV of methanol was passed through the resin column at a flow rate of 1 BV / h for alcohol analysis, and then 1-2 times the volume of the resin with a 1 mol / L sodium hydroxide solution was used for alkali analysis at a flow rate of 1-2 BV / h.

[0011] Moreover, after step S4 is completed, methanol with a volume of 1-2 times the resin volume is used to pass through the resin column at a flow rate of 1-2BV / h for alcohol analysis, and then 1-2 times the resin volume of 1 mol / L sodium hydroxide solution is used for alkali analysis at a flow rate of 1BV / h.

[0012] Moreover, after step S4 is completed, methanol with a volume of 1-2 times the volume of the resin is used to pass through the resin column at a flow rate of 2BV / h for alcohol analysis, and then 1-2 times the volume of the resin is used. 1 mol / L sodium hydroxide solution is used at a flow rate of 1BV / h for alkali analysis.

[0013] Compared with the prior art, the advantages of the present invention are: 1. The present invention adopts a thin film evaporator continuous feeding drying to replace the existing in-tank vacuum drying device. The thin film evaporator continuous feeding drying process is that the reaction liquid continuously enters the thin film evaporator for vacuum distillation, the reaction liquid is forced to form a film through the rotary scraper of the thin film evaporator, and the falling film distillation is performed at a high speed, thereby achieving the purpose of continuous drying; the traditional in-tank vacuum distillation process is that the reaction liquid is once injected into an enamel tank for vacuum distillation, and the distillation rate gradually decreases with the change of the volume and viscosity of the feed liquid. The thin film evaporator continuous drying method has higher heat transfer efficiency than the traditional drying method, the feed liquid has a short residence time at high temperature, and the evaporation speed is fast, which greatly shortens the evaporation time, and significantly improves the production efficiency while reducing energy consumption and improving the working environment.

[0014] 2. The present invention uses resin to decolorize the adjusted dissolved solution of D-p-hydroxyphenylglycine methyl ester hydrochloride instead of traditional activated carbon decolorization, utilizing the characteristic of the resin being recyclable, effectively reducing the production cost, avoiding the generation of a large amount of hazardous waste by traditional activated carbon decolorization and the harm of dust to the human body during use by personnel, greatly improving the working environment of the staff, and meeting the national requirements for green environmental protection processes.

[0015] 3. The technical solution of the present invention has substantially the same purity and yield of the decolorized liquid as those of the prior art. The fastest drying time is 7 minutes and 50 seconds, while the drying time of the prior art is 1 hour and 22 minutes, which greatly improves the drying speed. DETAILED DESCRIPTION

[0016] Example 1

[0017] A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride comprises the following steps: S1. Continuous drying of the reaction liquid: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction, controlling the temperature of the thin film evaporator to 40°C, the vacuum degree ≤-0.080MPa, and the rotation speed to 100rpm, and continuously injecting the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid into the thin film evaporator to obtain a concentrated solution and a condensate; when the content of D-p-hydroxyphenylglycine methyl ester hydrochloride in the concentrated solution is 450mg / mL and the purity is ≥98%, the feeding is completed and the concentrated solution is collected; S2. Adjust pH: When the temperature of the concentrated solution drops to 15°C, use a weak alkaline solution to adjust the pH to 1.0 to obtain the adjusted dissolved solution. S3, resin decolorization: the adjusted solution is passed through the resin column at a flow rate of 2BV / h, and the flow is stopped when the total flow rate reaches 10BV, and the decolorization is completed to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride decolorized solution; S4, recovery: use 0.5 times the volume of the resin drinking water to top wash the resin column at a flow rate of 1BV / h, and add the top wash water into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorizing solution, mix well, and obtain the D-p-hydroxyphenylglycine methyl ester hydrochloride treated solution, and the treatment is completed.

[0018] Furthermore, in step S3, the weak alkaline solution is aqueous ammonia.

[0019] Further, after step S4 is completed, methanol in an amount equal to 1 times the volume of the resin is used to pass through the resin column at a flow rate of 1 BV / h for alcohol analysis, and then 1 mol / L sodium hydroxide solution in an amount equal to 1 times the volume of the resin is used to perform alkali analysis at a flow rate of 1 BV / h.

[0020] Example 2 A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride comprises the following steps: S1, continuous drying of the reaction liquid: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction, controlling the temperature of the thin film evaporator to 80°C, the vacuum degree ≤-0.080MPa, and the rotation speed to 200rpm, and continuously injecting the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid into the thin film evaporator to obtain a concentrated solution and a condensate; when the content of D-p-hydroxyphenylglycine methyl ester hydrochloride in the concentrated solution is 500mg / mL and the purity is ≥98%, the feeding is completed and the concentrated solution is collected; S2. Adjust pH: When the temperature of the concentrated solution drops to 20°C, use a weak alkaline solution to adjust the pH to 1.5 to obtain the adjusted dissolved solution. S3, resin decolorization: the adjusted solution is passed through the resin column at a flow rate of 4BV / h, and the flow is stopped when the total flow rate reaches 15BV, and the decolorization is completed to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride decolorized solution; S4, recovery: use 1.5 times the volume of the resin drinking water to top wash the resin column at a flow rate of 2BV / h, and add the top wash water into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorizing solution, mix well, and obtain the D-p-hydroxyphenylglycine methyl ester hydrochloride treated solution, and the treatment is completed.

[0021] Furthermore, in step S3, the weak alkaline solution is aqueous ammonia.

[0022] Further, after step S4 is completed, methanol in an amount twice the volume of the resin is used to pass through the resin column at a flow rate of 2 BV / h for alcohol analysis, and then 1 mol / L sodium hydroxide solution in an amount twice the volume of the resin is used to perform alkali analysis at a flow rate of 2 BV / h.

[0023] Example 3 A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride comprises the following steps: S1. Continuous drying of the reaction liquid: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction, controlling the temperature of the thin film evaporator to 60°C, the vacuum degree ≤-0.080MPa, and the rotation speed to 150rpm, and continuously injecting the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid into the thin film evaporator to obtain a concentrated solution and a condensate; when the content of D-p-hydroxyphenylglycine methyl ester hydrochloride in the concentrated solution is 480mg / mL and the purity is ≥98%, the feeding is completed and the concentrated solution is collected; S2. Adjust pH: When the temperature of the concentrated solution drops to 18°C, use a weak alkaline solution to adjust the pH to 1.2 to obtain the adjusted dissolved solution. S3, resin decolorization: the adjusted solution is passed through the resin column at a flow rate of 3BV / h, and the flow is stopped when the total flow rate reaches 12BV, and the decolorization is completed to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride decolorized solution; S4, recovery: use 1BV of resin volume of process drinking water at a flow rate of 1BV / h to top wash the resin column, merge the top wash water into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorizing solution, mix evenly, obtain D-p-hydroxyphenylglycine methyl ester hydrochloride treated solution, and the treatment is completed.

[0024] Furthermore, in step S3, the weak alkaline solution is aqueous ammonia.

[0025] Further, after step S4, 1.5 times the volume of the resin is used as methanol, and the flow rate is 1.5 BV / h to pass through the resin column for alcohol analysis, and then 1.5 times the volume of the resin is used as 1 mol / L sodium hydroxide solution at a flow rate of 1.5 BV / h for alkali analysis.

[0026] Comparative Example This comparative example adopts the traditional can vacuum drying, which is as follows: S1. Take 1100 mL of the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction solution obtained by the esterification reaction, detect that the purity of D-p-hydroxyphenylglycine methyl ester hydrochloride is 98.5%, add it into a distillation flask, control the evaporation temperature to 60°C and the vacuum degree to -0.085 MPa to start reduced pressure distillation, and after 1 hour and 22 minutes, reduce the pressure to distill until the system has almost no fluidity, collect 560 mL of condensate, stop distillation, remove the heat source, neutralize and incinerate the condensate, and collect the concentrate; S2. Add 200 mL of process drinking water to the concentrate to obtain 706.5 mL of dissolved solution. Send the sample for HPLC detection to find that the purity of methyl ester hydrochloride is 98.5% and the content is 426 mg / mL.

[0027] S2. The temperature of the dissolved liquid was cooled to 18.5°C, and the pH value was adjusted to 1.21 with aqueous ammonia. 5.5 g of activated carbon was added for decolorization for 30 min. The carbon was removed by filtration with a 0.45 μm filter membrane. The liquid was filtered until no liquid was dripped. The activated carbon was top-washed with 40 mL of process drinking water and added into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorization liquid to obtain 741.4 mL of decolorization liquid. The purity of L-p-hydroxyphenylglycine methyl ester hydrochloride was 98.8% and the content was 405 mg / mL by HPLC. The decolorization yield was 99.79%, and the waste activated carbon was treated as solid waste.

[0028] Experimental Section Experiment 1 (1) Continuous drying of the reaction liquid: 1100 mL of the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction was taken, and the purity of D-p-hydroxyphenylglycine methyl ester hydrochloride was detected to be 98.5%. The temperature of the thin film evaporator was controlled at 60°C, the vacuum degree was -0.085 MPa, and the rotation speed was 150 rpm. The distillation of the reaction liquid was started. After 8 minutes, the feeding was completed, and the concentrated liquid and condensate were 615 mL and 479 mL respectively. The concentrated liquid was sampled and tested for the content of D-p-hydroxyphenylglycine methyl ester hydrochloride, which was 480.1 mg / mL and the purity was 98.8%; (2) Resin decolorization: The concentrated solution was cooled to 20.0°C, and the pH value was adjusted to 1.21 with an aqueous ammonia solution to obtain 647 mL of the adjusted solution. The temperature was controlled at 18°C ​​and the solution was passed through a resin column (pre-loaded with a 50 mL resin column) at a flow rate of 150 mL / h. After decolorization, 50 mL of process drinking water was used to top-wash the resin column at a flow rate of 50 mL / h. The top-wash water was added to the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorization solution. The decolorization solution was mixed evenly and the measured volume was 700 mL. The D-p-hydroxyphenylglycine methyl ester hydrochloride content was 421.1 mg / mL and the purity was 98.8%. The decolorization yield was 99.91%.

[0029] (3) Resin column analysis: At room temperature, 50 mL of methanol was passed through the resin column at a flow rate of 50 mL / h for alcohol analysis. The alcohol analysis solution was 50.0 mL, colorless. 1 mol / L sodium hydroxide solution was then introduced at a flow rate of 50 mL / h for alkaline analysis. The amount of 1 mol / L sodium hydroxide solution used for analysis was 50 mL.

[0030] Experiment 2 (1) Continuous drying of the reaction liquid: 1100 mL of the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction was taken, and the purity of D-p-hydroxyphenylglycine methyl ester hydrochloride was detected to be 98.3%. The temperature of the thin film evaporator was controlled at 60°C, the vacuum degree was -0.085 MPa, and the rotation speed was 150 rpm. The distillation of the reaction liquid was started. After 7 minutes and 50 seconds, the feeding was completed, and the concentrated liquid and condensate were 612 mL and 480 mL respectively. The concentrated liquid was sampled and tested for the content of D-p-hydroxyphenylglycine methyl ester hydrochloride, which was 485.1 mg / mL and the purity was 98.5%; (2) Resin decolorization: The concentrated solution was cooled to 20.0°C, and the pH value was adjusted to 1.23 with an aqueous ammonia solution to obtain 653 mL of the adjusted solution. The temperature was controlled at 18°C ​​and the solution was passed through a resin column (pre-loaded with a 50 mL resin column) at a flow rate of 150 mL / h. After decolorization, 50 mL of process drinking water was used to top-wash the resin column at a flow rate of 50 mL / h. The top-wash water was added to the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorization solution. The decolorization solution was mixed evenly and the measured volume was 703 mL. The D-p-hydroxyphenylglycine methyl ester hydrochloride content was 420.27 mg / mL and the purity was 98.9%. The decolorization yield was 99.80%.

[0031] (3) Resin column analysis: At room temperature, 50 mL of methanol was passed through the resin column at a flow rate of 50 mL / h for alcohol analysis, and 50.0 mL of alcohol analysis solution was collected, which was colorless. 1 mol / L sodium hydroxide solution was then introduced at a flow rate of 50 mL / h for alkaline analysis, and the amount of 1 mol / L sodium hydroxide solution used for analysis was 50 mL.

[0032] The yields of the comparative example and experiments 1-2 were measured respectively, and the experimental data were compared, as shown in Table 1.

[0033] Table 1 Comparison of comparative examples and experiments 1 and 2

[0034] It can be seen from Table 1 that experiments 1 and 2 adopt the technical scheme of the present invention, and the purity and yield of the obtained decolorized liquid are basically consistent with those of the comparative example, and the drying time is only 8 minutes and 7 minutes and 50 seconds, while the drying time of the comparative example is 1 hour and 22 minutes, which is more than ten times that of experiments 1 and 2. With the same technical effect, the evaporation rate of the present invention is significantly accelerated, the evaporation time is greatly shortened, and the production efficiency is improved while reducing energy consumption and improving the working environment; at the same time, the present invention uses resin to replace traditional activated carbon decolorization, and utilizes the characteristics of resin that can be recycled and reused, which effectively reduces production costs, does not generate solid waste, avoids the generation of a large amount of hazardous waste by traditional activated carbon decolorization and the harm of dust to the human body during use by personnel, greatly improves the working environment of the staff, and meets the national requirements for green environmental protection processes.

Claims

1. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride, characterized in that: The steps include: S1, continuous drying of the reaction liquid: taking the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid obtained by the esterification reaction, controlling the temperature of the thin film evaporator to 40-80°C, the vacuum degree ≤-0.080MPa, and the rotation speed to 100-200rpm, and continuously injecting the D-p-hydroxyphenylglycine methyl ester hydrochloride reaction liquid into the thin film evaporator to obtain a concentrated solution and a condensate; when the content of D-p-hydroxyphenylglycine methyl ester hydrochloride in the concentrated solution is 450-500mg / mL and the purity is ≥98%, the feeding is completed and the concentrated solution is collected; S2. Adjust pH: When the temperature of the concentrated solution drops below 45°C, use a weak alkaline solution to adjust the pH to 1.0-1.5 to obtain the adjusted dissolved solution. S3, resin decolorization: the adjusted solution is passed through the resin column at a flow rate of 2-4BV / h. When the total flow rate is 10-15BV, the flow is stopped, the decolorization is completed, and the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorization solution is collected; S4, recovery: use 0.5-1.5 times the volume of the resin drinking water to top wash the resin column at a flow rate of 1-2BV / h, and add the top wash water into the D-p-hydroxyphenylglycine methyl ester hydrochloride decolorizing solution, mix well, and obtain the D-p-hydroxyphenylglycine methyl ester hydrochloride treated solution, and the treatment is completed.

2. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: In the step S1, the temperature of the thin film evaporator is controlled to be 60°C.

3. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: In step S2, when the temperature of the concentrated solution drops to 15-20°C, the pH value is adjusted to 1.2 with a weak alkaline solution to obtain an adjusted dissolved solution.

4. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: In step S3, the weak alkaline solution is aqueous ammonia.

5. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: In the step S3, the resin is decolorized by passing the adjusted dissolved liquid through the resin column at a flow rate of 3 BV / h, and the flow is stopped when the total flow rate reaches 12 BV.

6. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In the step S4, the resin column is top washed with process drinking water having a resin volume of 1 BV at a flow rate of 1 BV / h.

7. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 1, characterized in that: After step S4, methanol in an amount 1-2 times the volume of the resin is used to pass through the resin column at a flow rate of 1-2 BV / h for alcohol analysis, and then 1-2 times the volume of the resin is used to perform alkali analysis at a flow rate of 1-2 BV / h with 1 mol / L sodium hydroxide solution.

8. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: After step S4, 2 BV of methanol is passed through the resin column at a flow rate of 1 BV / h for alcohol analysis, and then 1 mol / L sodium hydroxide solution of 1-2 times the volume of the resin is used for alkali analysis at a flow rate of 1-2 BV / h.

9. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride as claimed in claim 1, characterized in that: After step S4, methanol in an amount 1-2 times the volume of the resin is used to pass through the resin column at a flow rate of 1-2 BV / h for alcohol analysis, and then 1-2 times the volume of the resin is used to perform alkali analysis at a flow rate of 1 BV / h with 1 mol / L sodium hydroxide solution.

10. A post-treatment process for D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 1, characterized in that: After step S4, methanol in an amount 1-2 times the volume of the resin is used to pass through the resin column at a flow rate of 2 BV / h for alcohol analysis, and then 1 mol / L sodium hydroxide solution in an amount 1-2 times the volume of the resin is used to perform alkali analysis at a flow rate of 1 BV / h.

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