Synthesis method of florfenicol intermediate (1R, 2R)-p-methylsulfonyl phenyl serinol

Abstract

The invention provides a florfenicol intermediate (1R, 2R)-p-methylsulfonyl phenyl serinol synthesis method, which comprises: placing water and D-ethyl ester in a synthesis device, uniformly stirring, adding a catalyst and a reducing agent, maintaining the pH value of a reaction system to be 7-9, and carrying out a full reaction to synthesize a final product. And after the reaction is finished, filtering, cooling to 5-20 DEG C, and centrifugally separating to obtain a target product. The synthesis method is high in yield, simple in process, safe, efficient and easy for industrial production, the synthesis device provided by the invention can quickly and effectively synthesize D-alcohol, and the production efficiency and the production quality of the D-alcohol are greatly improved.

Description

Technical Field

[0001] The invention belongs to the field of veterinary drug raw material synthesis, and in particular relates to a method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol. Background Art

[0002] Florfenicol is a broad-spectrum antibacterial agent that is widely used in veterinary clinical practice to prevent and treat Gram-positive, Gram-negative and thiamphenicol-resistant bacterial diseases. It has a broad antibacterial spectrum, good absorption, and wide distribution in the body. It does not contain nitro groups and will not cause dose-related, reversible bone marrow suppression or irreversible aplastic anemia. It is also not teratogenic, carcinogenic, or mutagenic.

[0003] (1R,2R)-p-methylsulfonylphenylserinol, referred to as D-alcohol, is an important raw material for the synthesis of florfenicol. The existing technology often uses ethanol, methanol, and other alcohols as solvents. In the case of incomplete nitrogen replacement in these reaction systems, alcohol vapors are easy to form explosive mixtures with air. During the reduction reaction using sodium borohydride, there is a violent release of heat. This high heat energy has the hazard of causing combustion and explosion. When water is used as a solvent, the yield of the synthetic product is high and the quality is good in the laboratory stage, but in large-scale production, the yield of D-alcohol is low and the quality is poor. Therefore, we urgently need to develop a synthesis method with high yield, simple process, safety and efficiency. Summary of the invention

[0004] In view of this, the present invention aims to provide a method for synthesizing florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol to solve the problems of strong toxicity, high safety risk and low yield in the existing production process.

[0005] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0006] A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol, wherein water and D-ethyl ester are placed in a synthesis device, stirred evenly, a catalyst and a reducing agent are added, the pH of the reaction system is maintained between 7 and 9, and a final product is synthesized after sufficient reaction.

[0007] Furthermore, the catalyst is calcium chloride.

[0008] Furthermore, the reducing agent is sodium borohydride or potassium borohydride.

[0009] Furthermore, the method of maintaining the pH of the reaction system between 7 and 9 is to add a reducing agent and an acidic aqueous solution at the same time.

[0010] Furthermore, the synthesis device includes a reduction reactor, the top of which is connected to a configuration reactor, a dropping tank, a first feeder and a feeding bin, as well as a water source and a N2 source through pipelines, respectively; the water source and the N2 source are also connected to the configuration reactor through pipelines, and the configuration reactor is connected to a second feeder through a pipeline; the discharge port at the bottom of the reduction reactor is connected to a concentration crystallization reactor and a centrifuge in sequence.

[0011] Furthermore, the feeding bin is located at a position higher than the reduction reactor.

[0012] Furthermore, the reduction reaction kettle includes a kettle body and a cover body fixedly connected to the opening at the top of the kettle body, a collecting plate is hung and fixed at the upper side of the interior of the kettle body, a through hole is opened in the middle of the collecting plate, a rotatable stirring mechanism is provided inside the kettle body, the stirring mechanism includes a rotating rod vertically passed through the through hole, a first stirring paddle located below the collecting plate and a second stirring paddle located above the collecting plate are fixedly connected to the rotating rod, a gap is provided between the through hole and the rotating rod, a first feed port, a second feed port, a third feed port, a fourth feed port, a fifth feed port and a sixth feed port are provided on the upper side of the cover body, the first feed port is connected to the configuration kettle, the second feed port is connected to the dripping tank, the third feed port is connected to the first feeder, the fourth feed port is connected to the feeding bin, the fifth feed port is connected to the water source, and the sixth feed port is connected to the N2 source.

[0013] Furthermore, an L-shaped connecting edge is fixedly connected along the circumferential inner wall at the upper side of the interior of the kettle body, the bottom of the collecting plate is concave downward, and an inverted L-shaped overlapping edge is arranged outwardly on the top circumferentially, and the overlapping edge is overlapped and fixed in the connecting edge. Furthermore, a motor is fixedly connected to the upper side of the cover body, and the output end of the motor is fixedly connected to the rotating rod.

[0014] Furthermore, a sampling port is provided at the bottom of the kettle body, and a switch valve is arranged on the sampling port.

[0015] Compared with the prior art, the present invention has the following advantages:

[0016] The synthesis method provided by the invention has high yield, simple process, safety and high efficiency, and solves the technical problems of poor quality and low yield of the product D-alcohol obtained in the prior art.

[0017] The synthesis device provided by the invention can synthesize D-alcohol quickly and effectively, thereby greatly improving its production efficiency and production quality.

[0018] The reduction reaction kettle provided by the present invention is provided with a collecting plate inside to preliminarily mix the materials put into the kettle body, and in the process, the second stirring paddle is used to stir the materials so that the materials are preliminarily mixed to a certain degree of uniformity, and then the materials fall through the through hole and are thoroughly stirred by the first stirring paddle, thereby effectively improving the solution mixing and reaction speed. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0020] Figure 1 The schematic diagram of the synthesis device of florfenicol intermediate (1R,2R)-p-methylsulfonylphenylserinol;

[0021] Figure 2 It is a schematic diagram of the structure of the reduction reactor;

[0022] Figure 3 is a schematic diagram of the structure of the second stirring paddle;

[0023] Figure 4 Schematic diagram of the preparation method of florfenicol intermediate.

[0024] Description of reference numerals:

[0025] 1. Reduction reaction kettle; 11. Kettle body; 1101. Discharge port; 1102. Sampling port; 12. Cover body; 13. Collecting plate; 1301. Overlap edge; 1302. Handle; 1303. Through hole; 14. Connecting edge; 15. Rotating rod; 16. First stirring paddle; 1601. Connecting frame; 1602. Connecting rod; 17. Second stirring paddle; 1701. Connecting cylinder; 1702. Stirring rod; 18. Jacket; 19. Motor; 110. Bolt and nut pair; 2. Configuration kettle; 3. Second feeder; 4. Dropping tank; 5. First feeder; 6. Feeding bin; 7. Concentration crystallization kettle; 8. Centrifuge. DETAILED DESCRIPTION

[0026] The following specific descriptions are exemplary and are intended to provide further explanation of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements fall within the protection scope of the present invention.

[0027] Unless otherwise specified, the experimental methods used in the following experimental examples are all conventional methods; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0028] Example 1 Structure of the synthesis device

[0029] like Figure 1As shown, a synthesis device of florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol comprises a reduction reactor 1, the top of which is connected to a configuration reactor 2, a dropping tank 4, a first feeder 5 and a feeding bin 6, as well as a water source and a N2 source through pipelines, respectively; the water source and the N2 source are also connected to the configuration reactor 2 through pipelines, and the configuration reactor 2 is connected to a second feeder 3 through a pipeline; the discharge port 1101 at the bottom of the reduction reactor 1 is connected to a concentration crystallization reactor 7 and a centrifuge 8 in sequence.

[0030] The location of the feeding bin 6 is higher than the location of the reduction reactor 1 .

[0031] like Figure 2 As shown, the reduction reaction kettle 1 includes a kettle body 11 and a cover body 12 fixedly connected to the top opening of the kettle body 11, a collecting plate 13 is hung and fixed at the upper side of the inside of the kettle body 11, a through hole 1303 is opened in the middle of the collecting plate 13, a rotatable stirring mechanism is arranged inside the kettle body 11, and the stirring mechanism includes a rotating rod 15 vertically passing through the through hole 1303, a first stirring paddle 16 located below the collecting plate 13 and a second stirring paddle 17 located on the upper side of the collecting plate 13 are fixedly connected to the rotating rod 15, a gap is provided between the through hole 1303 and the rotating rod 15, and a first feed port, a second feed port, a third feed port, a fourth feed port, a fifth feed port, a sixth feed port ( Figure 2 The first feed port is connected to the configuration kettle 2, the second feed port is connected to the dropping tank 4, the third feed port is connected to the first feeder 5, the fourth feed port is connected to the feeding bin 6, the fifth feed port is connected to the water source, and the sixth feed port is connected to the N2 source.

[0032] An L-shaped connecting edge 14 is fixedly connected to the circumferential inner wall at the upper side of the kettle body 11 . The bottom of the collecting plate 13 is recessed downward to facilitate material collection. An inverted L-shaped overlapping edge 1301 is provided outwardly on the top circumferentially. The overlapping edge 1301 is overlapped and fixed in the connecting edge 14 .

[0033] A rubber ring (not shown) is fixedly connected to the inner side of the vertical section of the overlapping edge 1301 . The rubber ring is extruded and arranged between the overlapping edge 1301 and the connecting edge 14 , so that the collecting plate 13 is fixedly connected and overlapped on the connecting edge 14 .

[0034] A plurality of handles 1302 are evenly arranged on the upper side of the overlapping edge 1301 to facilitate the disassembly and assembly of the aggregate plate 13 on the connecting edge 14 .

[0035] A motor 19 is fixedly connected to the upper side of the cover body 12, and the output end of the motor 19 is fixedly connected to the rotating rod 15. The rotating rod 15 is driven to rotate by the motor 19.

[0036] The first stirring paddle 16 includes a U-shaped connecting frame 1601 and a plurality of connecting rods 1602 uniformly fixed in the connecting frame 1601. The middle of the connecting plate and the bottom of the connecting frame 1601 are fixed to the rotating rod 15. In this embodiment, the connecting plate and the bottom of the connecting frame 1601 are fixed to the rotating rod 15 by welding.

[0037] like Figure 3 As shown, the second stirring paddle 17 includes a connecting tube 1701, and a stirring rod 1702 is symmetrically fixed to the bottom of the connecting tube 1701. The upper part of the connecting tube 1701 is higher than the collecting plate 13 and is fixed to the rotating rod 15 by bolts, and the bolts are installed to avoid being immersed in the mixed liquid on the collecting plate 13 for a long time. In this embodiment, the connecting tube 1701 is provided to facilitate the disassembly and assembly of the second stirring paddle 17, and to facilitate the disassembly and assembly of the stirring unit and the collecting plate 13 in the kettle body 11.

[0038] A sampling port 1102 is also provided at the bottom of the kettle body 11 , and a switch valve is provided on the sampling port 1102 for sampling, so that the reaction progress inside the kettle body 11 can be known at any time.

[0039] A jacket 18 is disposed outside the kettle body 11 , and a heating coil and a cooling coil disposed inside the jacket 18 can heat and cool the kettle body 11 .

[0040] In this embodiment, the kettle body 11 is further provided with a pH meter, a temperature sensor and a pressure gauge for monitoring the internal environment of the kettle body 11 .

[0041] In this embodiment, a sealing ring is provided between the cover body 12 and the kettle body 11 , and the cover body 12 and the kettle body 11 are fixed together by a plurality of bolt and nut pairs 110 .

[0042] Example 2. Working process of the synthesis device

[0043] Synthesis methods such as Figure 4 The process is to control the amount of water added at the water source through a flow meter, add water to the configuration kettle 2, and add the reducing agent to the configuration kettle 2 through the second feeder 3, and stir and dissolve it through the stirring unit in the configuration kettle 2;

[0044] Control the amount of water added at the water source, add water to the reduction reactor 1, add D-ethyl ester to the reduction reactor 1 through the high-level feeding bin 6, add calcium chloride to the reduction reactor 1 through the first feeder 5, continuously introduce N2 through the N2 source, slowly press the reducing agent into the reduction reactor 1, automatically control the pH value through the pH meter on the reduction reactor 1, add the acidic aqueous solution in the dropping tank 4, and keep the pH in the reduction reactor 1 at 8±1; during the reaction, take samples at the sampling port 1102 to monitor the reaction process; after the reaction is completed, add acid through the dropping tank 4 to quench the reaction. After the reaction is quenched, the reacted solution is pressed into the concentration and crystallization kettle 7 through the pipeline, and after being concentrated to a certain degree, the N2 is restored to normal pressure, methanol is added, and then cooled to crystallize at a lower temperature; finally, the centrifuge 8 is completed and the material is discharged after centrifugation and drying.

[0045] In the reduction reactor 1, after each liquid material is added from the corresponding feed port, it first falls onto the collecting plate 13 and is preliminarily mixed under the stirring action of the second stirring paddle 17. Of course, in this process, the material may also fall from the through hole 1303 without being stirred. When the material input is large and greater than the falling amount of the through hole 1303, the second stirring paddle 17 is used for effective stirring, and the liquid falls from the through hole 1303 to the bottom of the collecting plate 13. As more and more material is added, the mixed liquid continues to fall through the through hole 1303, and the liquid at the lower part of the reactor body 11 accumulates more and more until the material is completely added. In this process and in the process of reacting after the material is dropped to achieve the expected result, the solution is stirred by the first stirring paddle 16 to make the solution react more evenly and quickly.

[0046] Comparative Example 1. Components in the Synthesis Method of D-Alcohol

[0047] According to the working process of the synthesis device in Example 2, 8 kg of purified water and 1 kg of D-ethyl ester were added to the reactor 2 and stirred evenly; 0.5 kg of calcium chloride was added to the first feeder, and 11% sodium borohydride solution was slowly added dropwise to the second feeder, and 50% acetic acid aqueous solution was added dropwise to maintain the system pH = 7-9 to obtain white solid D-alcohol with a yield of 90.1% and a purity of 98.2%. The main impurity was D-acid.

[0048] Comparative Example 2

[0049] According to the working process of the synthesis device in Example 2, 8 kg of purified water and 1 kg of D-ethyl ester were added to the reactor 2 and stirred evenly; 0.5 kg of calcium chloride was added to the first feeder, and 11% potassium borohydride solution was slowly added dropwise to the second feeder, and 18% hydrochloric acid aqueous solution was added dropwise to maintain the system pH = 7-9 to obtain white solid D-alcohol with a yield of 88.7% and a purity of 97.6%. The main impurity was D-acid.

[0050] Comparative Example 3

[0051] According to the working process of the synthesis device in Example 2, 80 kg of purified water and 10 kg of D-ethyl ester were added to the reactor 2 and stirred evenly; 5 kg of calcium chloride was added to the first feeder, and 11% sodium borohydride solution was slowly added dropwise to the second feeder, and 50% acetic acid aqueous solution was added dropwise to maintain the system pH = 7-9 to obtain white solid D-alcohol with a yield of 92.1% and a purity of 97.9%. The main impurity was D-acid.

[0052] Comparative Example 4

[0053] According to the working process of the synthesis device in Example 2, 80 kg of purified water and 10 kg of D-ethyl ester were added to the reactor 2 and stirred evenly; 5 kg of calcium chloride was added to the first feeder 5, and 11% sodium borohydride solution was slowly added dropwise to the second feeder, and 50% acetic acid aqueous solution was added dropwise to maintain the system pH = 7-9 to obtain white solid D-alcohol with a yield of 90.3% and a purity of 98.1%. The main impurity was D-acid.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol, characterized in that: The synthesis method comprises placing water and D-ethyl ester in a synthesis device, stirring evenly, adding a catalyst and a reducing agent, maintaining the pH of the reaction system between 7 and 9, and synthesizing the final product after sufficient reaction.

2. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 1, characterized in that: The catalyst is calcium chloride.

3. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 1, characterized in that: The reducing agent is sodium borohydride or potassium borohydride.

4. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 1, characterized in that: The method of maintaining the pH of the reaction system between 7 and 9 is to add a reducing agent and an acidic aqueous solution at the same time.

5. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 1, characterized in that: The synthesis device includes a reduction reactor, the top of which is connected to a configuration reactor, a dropping tank, a first feeder and a feeding bin, as well as a water source and a N2 source through pipelines, respectively; the water source and the N2 source are also connected to the configuration reactor through pipelines, and the configuration reactor is connected to the second feeder through a pipeline; the discharge port at the bottom of the reduction reactor is connected to a concentration crystallization reactor and a centrifuge in sequence.

6. A method for synthesizing a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 5, characterized in that: The location of the feeding bin is higher than the location of the reduction reactor.

7. A synthesis device for a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 5, characterized in that: The reduction reaction kettle comprises a kettle body and a cover body fixedly connected to the opening at the top of the kettle body, a collecting plate is hung and fixed at the upper side of the interior of the kettle body, a through hole is opened in the middle of the collecting plate, a rotatable stirring mechanism is arranged inside the kettle body, the stirring mechanism comprises a rotating rod vertically passing through the through hole, a first stirring paddle located below the collecting plate and a second stirring paddle located above the collecting plate are fixedly connected to the rotating rod, a gap is arranged between the through hole and the rotating rod, a first feed port, a second feed port, a third feed port, a fourth feed port, a fifth feed port and a sixth feed port are arranged on the upper side of the cover body, the first feed port is connected to the configuration kettle, the second feed port is connected to the dripping tank, the third feed port is connected to the first feeder, the fourth feed port is connected to the feeding bin, the fifth feed port is connected to the water source, and the sixth feed port is connected to the N2 source.

8. A synthesis device for the florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 7, characterized in that: An L-shaped connecting edge is fixedly connected to the circumferential inner wall at the upper side of the kettle body. The bottom of the collecting plate is concave downward, and an inverted L-shaped overlapping edge is arranged outwardly on the top. The overlapping edge is overlapped and fixed in the connecting edge.

9. A synthesis device for the florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 7, characterized in that: A motor is fixedly connected to the upper side of the cover body, and an output end of the motor is fixedly connected to the rotating rod.

10. A synthesis device for a florfenicol intermediate (1R, 2R)-p-methylsulfonylphenylserinol according to claim 7, characterized in that: A sampling port is also provided at the bottom of the kettle body, and a switch valve is arranged on the sampling port.

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