Continuous preparation process of D-p-hydroxyphenylglycine double salt

Abstract

The invention discloses a continuous preparation process of D-p-hydroxyphenylglycine double salt, which specifically comprises the following steps: mixing a resolving agent solution with a certain concentration and a DL-p-hydroxyphenylglycine solution according to a certain ratio, introducing the mixture into a continuous reactor, separating the reaction liquid by a solid-liquid separator to obtain a filter cake which is the double salt, and after the mother liquor is subjected to racemization treatment, DL-p-hydroxyphenylglycine is supplemented, and a DL-p-hydroxyphenylglycine solution with a certain concentration is prepared again for later use. After double salt dissociation, D acid is separated out, and the resolving agent is recycled to be prepared into a solution with a certain concentration again for use. Compared with a traditional intermittent preparation method, the preparation method disclosed by the invention is high in preparation efficiency, low in energy consumption, few in generated impurities and high in chiral purity of the product, ensures high optical purity of the D acid in the next step, and is suitable for industrial production.

Description

Technical Field

[0001] The present application relates to a pharmaceutical intermediate synthesis process, and in particular to a continuous preparation process for a D-p-hydroxyphenylglycine double salt. Background Art

[0002] L-p-hydroxyphenylglycine is not only an important fine chemical product and important pharmaceutical intermediate, but also an indispensable side chain acid in the synthesis of broad-spectrum antibiotics such as amoxicillin, cefadroxil, cefoperazone, cefuroxil and cefadroxil. The key raw material for the preparation of L-p-hydroxyphenylglycine is D-p-hydroxyphenylglycine double salt, which can be directly dissociated with alkali to obtain the final product D acid.

[0003] At present, there are few reports on the separate synthesis of D-p-hydroxyphenylglycine complex salt. The industrial synthesis method mainly adopts the intermittent method. The complex salt is only an intermediate in the whole process. The synthesis method is relatively complicated, with high energy consumption and low production capacity. The steps include high-temperature synthesis, low-temperature crystallization, crude product refining, etc. The production cost of this process no longer has an advantage in today's market competition. Therefore, it is necessary to invent a more efficient and energy-saving preparation process. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present application provides a continuous process for preparing D-p-hydroxyphenylglycine double salt.

[0005] The continuous preparation process of D-p-hydroxyphenylglycine double salt described in the technical solution of the present application has the following simple operation steps: S101, preparing a resolving agent solution with a certain concentration by mixing water and a resolving agent; preparing a resolving agent solution with a certain concentration by mixing water, an inorganic acid and d-p-hydroxyphenylglycine; S102, mixing the resolving agent solution and the d-p-hydroxyphenylglycine solution and reacting them to obtain a reaction solution; the molar ratio of the resolving agent to the d-p-hydroxyphenylglycine is 1:(1-4); the reaction residence time is (1-40) min; S103, performing solid-liquid separation on the reaction liquid. When the separated solid reaches a certain amount, the obtained reaction liquid switches the pipeline to the next solid-liquid separator. The pipeline can be switched between the two regularly for subsequent production; S104, washing the filter cake separated in S103 with a small amount of water and discharging the wet product to obtain a wet product, and vacuum drying the wet product to obtain a product; S105, racemize the mother liquor separated in S103, and add d-p-hydroxyphenylglycine to re-form a d-p-hydroxyphenylglycine solution of a certain concentration; mix the d-p-hydroxyphenylglycine solution with a resolving agent solution, and repeat S102, S103, S104 and S105 to cyclically prepare the product.

[0006] The continuous preparation process of a D-p-hydroxyphenylglycine double salt described in the technical solution of the present application has the following reaction equation: The double salt is synthesized by reacting 4-hydroxyphenylglycine with a resolving agent:

[0007] Wherein, R1=H, CH3, CH2CH3; R2=H, CH3, CH2CH3; Further, the resolving agent is dextrorotatory p-ethylbenzene ethanesulfonic acid, dextrorotatory phenylethanesulfonic acid, dextrorotatory o-methylbenzene ethanesulfonic acid, dextrorotatory p-methylbenzene ethanesulfonic acid or dextrorotatory dimethylbenzene ethanesulfonic acid, preferably dextrorotatory phenylethanesulfonic acid.

[0008] Furthermore, the molar ratio of the resolving agent to the racemic p-hydroxyphenylglycine is 1:(1-4); preferably 1:(2-3), and more preferably 1:(2.4-2.6).

[0009] Furthermore, the mass ratio of the resolving agent to water is 1:(5-10), preferably 1:(7-8).

[0010] Furthermore, the mass ratio of the mixed p-hydroxyphenylglycine to water is 1:(2-8), preferably 1:(4-5).

[0011] Furthermore, the reaction temperature in step S102 is (50-100)°C. The preferred temperature is (80-95)°C.

[0012] Furthermore, the resolving agent is a pure resolving agent or a resolving agent that is recovered and reused after dissociation and separation of D acid.

[0013] Furthermore, the rac-p-hydroxyphenylglycine is pure rac-p-hydroxyphenylglycine or rac-p-hydroxyphenylglycine recovered after racemization treatment.

[0014] In summary, the beneficial technical effects of the present application are as follows: the present application improves the reaction efficiency and shortens the reaction time by continuous feeding and continuous discharging; at the same time, the continuous preparation method is not affected by the size of the reaction scale and is easy to realize scaled-up production; and the reaction time and temperature are controlled during the continuous reaction process, so that the chiral purity of the double salt is improved, and the large amount of energy consumption of operations such as heating, cooling, crystallization and recrystallization is reduced, which reduces a large amount of energy consumption and labor costs for enterprises, significantly reduces the comprehensive production cost, and improves the market competitiveness of the final product D acid. The chiral purity of the double salt obtained in the present application is more than 99.5%, the double salt yield is more than 95% (based on d-p-hydroxyphenylglycine), and the loss of the resolving agent after recycling is less than 2%. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Schematic diagram of the continuous preparation process of D-p-hydroxyphenylglycine double salt in the embodiment. DETAILED DESCRIPTION

[0016] In order to express the purpose and technical solution of the present application more clearly, the present application is described in detail below in combination with reference examples and embodiments. Obviously, the described embodiments are only part of the embodiments of the present application, not all of them.

[0017] Para-hydroxyphenylglycine was purchased from Beijing Bailingwei Technology Co., Ltd. Example 1

[0018] Reference Figure 1 , the present application proposes a continuous preparation device for D-p-hydroxyphenylglycine complex salt, comprising at least two batching kettles, a feed pump, a continuous reactor, and at least two sets of solid-liquid separators. The device in this embodiment includes two batching kettles and two sets of solid-liquid separators, one of which is a splitting agent batching kettle, and the other is a mixed p-hydroxyphenylglycine batching kettle, and the two sets of solid-liquid separators are divided into a first solid-liquid separator and a second solid-liquid separator. Both batching kettles are connected to the feed pump and the feed port of the continuous reactor, and the discharge port of the continuous reactor and the liquid inlet ends of the two sets of solid-liquid separators can be connected and can be switched freely.

[0019] Based on the above-mentioned continuous preparation device, the present application proposes a continuous preparation process for D-p-hydroxyphenylglycine complex salt.

[0020] S101, add 1605 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine to a d-p-hydroxyphenylglycine batching kettle, mix to obtain a d-p-hydroxyphenylglycine solution; add 200 g of dextrorotatory p-methylbenzeneethanesulfonic acid and 1302 g of purified water to a resolving agent batching kettle, mix, heat to 75±5° C., and stir for 0.5 h to obtain a resolving agent solution; S102, adjusting the temperature of the continuous reactor to 90°C, feeding the resolving agent solution and the vortex p-hydroxyphenylglycine solution into the continuous reactor at a molar ratio of 1:2.4, mixing and reacting to obtain a reaction solution; the reaction residence time is 14 minutes; S103, performing solid-liquid separation on the reaction liquid; when the separated solid reaches the rated capacity of the solid-liquid separator, the obtained reaction liquid switches the pipeline to the second solid-liquid separator, and in subsequent production, the pipeline is regularly switched between the two sets of solid-liquid separators to ensure continuous discharge.

[0021] S104, the filter cake separated in S103 is rinsed with a small amount of water and then discharged to obtain a wet product, which is then vacuum dried to obtain a product double salt with a purity of 99.9%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.8%.

[0022] S105, racemize the mother liquor separated and produced in S103, detect the content of d-p-hydroxyphenylglycine, add d-p-hydroxyphenylglycine to re-formulate a d-p-hydroxyphenylglycine solution with the same concentration as in S101, dissociate the product double salt, separate the D acid, recover the splitting agent and add the splitting agent to the recovered splitting agent to re-formulate a splitting agent solution with the same concentration as in S101, repeat S102, S103, S104 and S105 to prepare the product in a cycle. Example 2

[0023] The difference from Example 1 is that: S101, 1605 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine are added to a d-p-hydroxyphenylglycine batching kettle and mixed to obtain a d-p-hydroxyphenylglycine solution; 186 g of dextrorotatory benzene ethyl sulfonic acid and 1302 g of purified water are added to a resolving agent batching kettle, mixed, heated to 75±5° C., and stirred for 0.5 h to obtain a resolving agent solution; S102, adjusting the temperature of the continuous reactor to 90°C, and then feeding the resolving agent solution and the vortex p-hydroxyphenylglycine solution in a molar ratio of 1:2.4 and mixing and reacting to obtain a reaction solution; the reaction residence time is 14 minutes; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.9%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.7%. Example 3

[0024] S101, the preparation method of the vortex p-hydroxyphenylglycine solution and the resolving agent solution is the same as that of Example 1. The temperature of the continuous reactor is adjusted to 50° C., and the resolving agent solution and the vortex p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.8%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.1%. Example 4

[0025] S101, the preparation method of the vortex p-hydroxyphenylglycine solution and the resolving agent solution is the same as that of Example 1. The temperature of the continuous reactor is adjusted to 100° C., and the resolving agent solution and the vortex p-hydroxyphenylglycine solution are mixed and reacted at a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.7%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.8%. Example 5

[0026] S101, the preparation method of the vortex p-hydroxyphenylglycine solution and the resolving agent solution is the same as that of Example 1. The temperature of the continuous reactor is adjusted to 80° C., and the resolving agent solution and the vortex p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.8%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.7%. Example 6

[0027] S101, the preparation method of the vortex p-hydroxyphenylglycine solution and the resolving agent solution is the same as that of Example 1. The temperature of the continuous reactor is adjusted to 90° C., and the resolving agent solution and the vortex p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:1 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.5%, wherein the chiral purity of D-p-hydroxyphenylglycine is 98.2%. Example 7

[0028] S101, the preparation method of the vortex p-hydroxyphenylglycine solution and the resolving agent solution is the same as that of Example 1. The temperature of the continuous reactor is adjusted to 90° C., and the resolving agent solution and the vortex p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.8%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.9%. Example 8

[0029] S101, 1605 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine are prepared into a d-p-hydroxyphenylglycine solution; 186 g of dextrorotatory benzene ethyl sulfonic acid and 930 g of purified water are mixed, the temperature is raised to 75±5° C., and the mixture is stirred for 0.5 h to prepare a d-p-hydroxyphenylglycine solution; the temperature of the continuous reactor is first adjusted to 90° C., and then the d-p-hydroxyphenylglycine solution and the d-p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.6%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.3%. Example 9

[0030] S101, 1605 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine are prepared into a d-p-hydroxyphenylglycine solution; 186 g of dextrorotatory benzene ethylsulfonic acid and 1860 g of purified water are mixed, the temperature is raised to 75±5° C., and the mixture is stirred for 0.5 h to prepare a d-p-hydroxyphenylglycine solution; the temperature of the continuous reactor is first adjusted to 90° C., and then the d-p-hydroxyphenylglycine solution and the d-p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.7%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.8%. Example 10

[0031] S101, 802 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine are prepared into a d-p-hydroxyphenylglycine solution; 186 g of dextrorotatory benzeneethylsulfonic acid and 1302 g of purified water are mixed, the temperature is raised to 75±5° C., and the mixture is stirred for 0.5 h to prepare a resolving agent solution; First, the temperature of the continuous reactor was adjusted to 90° C., and then the resolving agent solution and the cycloparahydroxyphenylglycine solution were mixed and reacted at a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time was 14 minutes; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.6%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.0%. Embodiment 11

[0032] S101, 3208 g of water, 235 g of concentrated sulfuric acid, and 401 g of d-p-hydroxyphenylglycine are prepared into a d-p-hydroxyphenylglycine solution; 186 g of dextrorotatory benzene ethyl sulfonic acid and 1302 g of purified water are mixed, the temperature is raised to 75±5° C., and the mixture is stirred for 0.5 h to prepare a d-p-hydroxyphenylglycine solution; the temperature of the continuous reactor is first adjusted to 90° C., and then the d-p-hydroxyphenylglycine solution and the d-p-hydroxyphenylglycine solution are mixed and reacted in a molar ratio of 1:2.4 to obtain a reaction solution; the reaction residence time is 14 min; The post-treatment method is the same as that in Example 1 to obtain a product with a purity of 99.8%, wherein the chiral purity of D-p-hydroxyphenylglycine is 99.9%.

[0033] The above-mentioned implementation mode is merely an explanation of the present application, and it is not a limitation of the present application. After reading this specification, a person skilled in the art can make non-creative modifications to the present implementation mode as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine, characterized in that: The preparation steps include: S101, preparing a resolving agent solution with a certain concentration by mixing water and a resolving agent; preparing a resolving agent solution with a certain concentration by mixing water, an inorganic acid and d-p-hydroxyphenylglycine; S102, mixing the resolving agent solution and the d-p-hydroxyphenylglycine solution and reacting them to obtain a reaction solution; the molar ratio of the resolving agent to the d-p-hydroxyphenylglycine is 1:(1-4); the reaction residence time is (1-40) min; S103, performing solid-liquid separation on the reaction liquid. When the separated solid reaches a certain amount, the obtained reaction liquid switches the pipeline to the next solid-liquid separator. The pipeline can be switched between the two regularly for subsequent production; S104, washing the filter cake separated in S103 with a small amount of water and discharging the wet product to obtain a wet product, and vacuum drying the wet product to obtain a product; S105, racemize the mother liquor separated in S103, and add d-p-hydroxyphenylglycine to re-form a d-p-hydroxyphenylglycine solution of a certain concentration; mix the d-p-hydroxyphenylglycine solution with a resolving agent solution, and repeat S102, S103, S104 and S105 to cyclically prepare the product.

2. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine as claimed in claim 1, characterized in that: The resolving agent is dextrorotatory p-ethylbenzene ethanesulfonic acid, dextrorotatory phenylethanesulfonic acid, dextrorotatory o-methylbenzene ethanesulfonic acid, dextrorotatory p-methylbenzene ethanesulfonic acid or dextrorotatory dimethylbenzene ethanesulfonic acid.

3. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine as claimed in claim 1, characterized in that: The mass ratio of the resolving agent to water in the resolving agent solution is 1:(5-10).

4. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine as claimed in claim 1, characterized in that: The mass ratio of d-p-hydroxyphenylglycine to water in the d-p-hydroxyphenylglycine solution is 1:(2-8).

5. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine as claimed in claim 1, characterized in that: The reaction temperature in step S102 is (50-100)°C.

6. A continuous process for preparing a double salt of D-p-hydroxyphenylglycine as claimed in claim 1, characterized in that: The resolving agent is a pure resolving agent or a resolving agent that is recovered and reused after dissociation and separation of D acid.

7. The continuous process for preparing a double salt of D-p-hydroxyphenylglycine according to claim 1, characterized in that: The rac-p-hydroxyphenylglycine is pure rac-p-hydroxyphenylglycine or rac-p-hydroxyphenylglycine recovered after racemization treatment.

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