Florfenicol intermediates

Abstract

The application discloses a florfenicol intermediate and belongs to the technical field of chemical synthesis. By adding aluminum magnesium hydrotalcite composite potassium carbonate as an alkaline catalyst in the preparation process of the florfenicol intermediate, the phenomenon that traditional pure potassium carbonate is easily dissolved and lost in glycerol solvent can be avoided, the prepared florfenicol intermediate has high purity and high yield; the aluminum magnesium hydrotalcite composite potassium carbonate is successively subjected to dimethyl sulfoxide stripping, methanol hydrothermal treatment and hexadecyl trimethyl ammonium bromide intercalation treatment, and modified aluminum magnesium hydrotalcite with a large specific surface area and interlayer spacing is obtained; and the modified aluminum magnesium hydrotalcite is used as a carrier to load potassium carbonate; the modified aluminum magnesium hydrotalcite is a layered structure, and the potassium carbonate is uniformly loaded in the interlayer space and the surface of the hydrotalcite; and the interlayer confinement effect can fix the potassium carbonate, thereby avoiding loss.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically florfenicol intermediates. Background Technology

[0002] Florfenicol, also known as fluprofen, is widely used for various Gram-positive and Gram-negative bacteria and microorganisms that produce antibodies against thiamphenicol. It is currently the best veterinary antibiotic in the world and is a new type of chloramphenicol antibacterial drug developed by Schering-Plough in the United States.

[0003] This product is a white crystalline powder, non-toxic and odorless, non-flammable, non-explosive, non-corrosive, non-oxidizing, non-anesthetic, and non-psychotropic. It is readily soluble in dimethylformamide and slightly soluble in water. It is mainly used to treat bacterial diseases in fish, cattle, and pigs. It was first approved for marketing in Japan in 1990. Its characteristics include a broad antibacterial spectrum, good absorption, and wide distribution in the body. In particular, it does not have the potential to cause aplastic anemia, and it is a widely used veterinary drug abroad. In Japan and Mexico, florfenicol is used as a feed additive for pigs to prevent and treat various bacterial diseases. Scanning electron microscopy showed that florfenicol, chloramphenicol, and thiamphenicol induced neutrophil morphology at percentages of 67%, 94%, and 32%, respectively, with florfenicol having a lower effect on neutrophil morphology than chloramphenicol. Based on the above, the development of new florfenicol veterinary drugs in my country is of practical significance.

[0004] my country's livestock and aquaculture industries hold a significant position globally, accounting for approximately 12% of the world's similar resources. Most diseases and deaths in livestock and aquatic animals are caused by bacterial infections. Florfenicol has shown significant therapeutic effects on this disease and has no potential to cause aplastic anemia, making it highly popular among livestock and aquaculture farmers.

[0005] Currently, pure potassium carbonate is widely used in industry as a basic catalyst for cyclization reactions, with glycerol as the reaction solvent. Pure potassium carbonate has become the mainstream choice due to its readily available raw materials and low cost. However, in practical applications, pure potassium carbonate is easily dissolved and lost in glycerol solvent due to potassium ion coordination stripping, resulting in a decrease in reaction rate, an increase in side reactions, and ultimately, a lower purity and yield of florfenicol intermediates. Summary of the Invention

[0006] The purpose of this invention is to provide a florfenicol intermediate. By adding aluminum-magnesium hydrotalcite composite potassium carbonate as an alkaline catalyst during the preparation of the florfenicol intermediate, the phenomenon of easy dissolution and loss of traditional pure potassium carbonate in glycerol solvent can be avoided, resulting in a florfenicol intermediate with high purity and high yield.

[0007] The objective of this invention can be achieved through the following technical solutions: The intermediate of florfenicol has the structural formula shown in Formula 1: Formula 1; Florfenicol intermediates are prepared via the following steps: Using methanol as solvent and potassium borohydride as reducing agent, the ester group in D-ester is reduced to a hydroxyl group. Then, under the catalysis of aluminum magnesium hydrotalcite composite potassium carbonate, the cyano group of benzyl nitrile undergoes nucleophilic addition with the amino group and then cyclizes with the hydroxyl group to obtain the florfenicol intermediate.

[0008] The reaction process is as follows: The specific preparation steps for florfenicol intermediates are as follows: D-ester, methanol, and potassium borohydride were added to a reduction vessel and reduced for 2-3 hours at 50-55℃ and 40-50 r / min. The methanol was then distilled, followed by the addition of 98% concentrated hydrochloric acid and deionized water. The mixture was cooled to -5℃ and kept at that temperature for 2-3 hours. After centrifugation at 1000-1200 r / min for 10-12 minutes, the product was washed 2-4 times with refrigerated ethanol to obtain a centrifuged wet product.

[0009] The centrifuged wet product was added to a cyclization vessel, followed by glycerol, aluminum-magnesium hydrotalcite composite potassium carbonate, and benzyl nitrile. The mixture was kept at 105-110℃ and 40-50 r / min for 10-12 h, then naturally cooled to room temperature. The product was crystallized in water and centrifuged at 1000-1200 r / min for 10-12 min. The product was washed 2-4 times with a 50-60% (w / w) frozen isopropanol solution and then vacuum dried at 60-70℃ for 1-2 h to obtain the florfenicol intermediate.

[0010] Furthermore, the mass ratio of the centrifuged wet product, glycerol, aluminum magnesium hydrotalcite composite potassium carbonate, benzyl nitrile, and isopropanol solution is 180-190:750-760:65-67:135-138:266-270.

[0011] Furthermore, the ratio of D-ester, methanol, potassium borohydride, concentrated hydrochloric acid, and deionized water is 200-200 kg: 480-490 kg: 56-58 kg: 168-170 kg: 1370-1380 kg.

[0012] Furthermore, the aluminum-magnesium hydrotalcite composite potassium carbonate is prepared through the following steps: Modified aluminum-magnesium hydrotalcite and potassium carbonate solution with a concentration of 1-1.2 mol / L were stirred and mixed at a ratio of 5-6 g: 100-120 mL at 500-600 r / min for 24-26 h, dried under vacuum at 60-70℃ for 1-2 h, and then calcined in a muffle furnace at 450-500℃ for 4-5 h to obtain aluminum-magnesium hydrotalcite composite potassium carbonate.

[0013] Furthermore, the modified aluminum-magnesium hydrotalcite is prepared through the following steps: Add aluminum-magnesium hydrotalcite, dimethyl sulfoxide, and deionized water to a reaction vessel at a ratio of 10-12 g: 200-220 mL: 20-22 mL. Stir at 80-85℃ and 400-500 r / min for 24-26 h. Allow to cool naturally to room temperature, centrifuge at 1000-1200 r / min for 10-12 min, filter, wash the precipitate 2-4 times with deionized water and anhydrous ethanol, and vacuum dry at 60-70℃ for 1-2 h to obtain pretreated aluminum-magnesium hydrotalcite.

[0014] Pretreated aluminum-magnesium hydrotalcite and methanol were added to a polytetrafluoroethylene hydrothermal reactor at a ratio of 8-10g:200-250mL. The reactor was hydrothermally reacted at 100-110℃ and 500-600r / min for 24-26h. After filtration, the filter cake was washed 2-4 times with anhydrous ethanol and deionized water and dried under vacuum at 60-70℃ for 1-2h to obtain hydrothermal aluminum-magnesium hydrotalcite.

[0015] Hydrothermal aluminum-magnesium hydrotalcite, hexadecyltrimethylammonium bromide, and methanol were added to a polytetrafluoroethylene hydrothermal reactor at a ratio of 6-7 g: 1-2 g: 200-250 mL. The reactor was hydrothermally reacted at 100-110 °C and 500-600 r / min for 24-26 h. After naturally cooling to room temperature, the reactor was centrifuged at 10000-12000 r / min for 3-4 min, filtered, and the filter cake was washed 2-4 times with methanol and deionized water. The filter cake was then vacuum dried at 60-70 °C for 1-2 h to obtain modified aluminum-magnesium hydrotalcite.

[0016] Furthermore, aluminum-magnesium hydrotalcite is prepared by co-precipitation using magnesium nitrate, aluminum nitrate, sodium hydroxide, and anhydrous sodium carbonate as raw materials. The specific preparation steps are as follows: Magnesium nitrate, aluminum nitrate, sodium hydroxide, and anhydrous sodium carbonate were added to a reaction vessel at a mass ratio of 15-17:7.5-8.5:1.05-1.18. The mixture was aged at 70-75℃ and 400-500 r / min for 20-22 h, centrifuged at 1000-1200 r / min for 10-12 min, filtered, and the precipitate was washed with deionized water until the final wash solution was neutral. The precipitate was then vacuum dried at 60-70℃ for 1-2 h to obtain aluminum magnesium hydrotalcite.

[0017] The beneficial effects of this invention are: 1. This invention uses aluminum-magnesium hydrotalcite composite potassium carbonate as an alkaline catalyst during the preparation of florfenicol intermediates, which avoids the easy dissolution and loss of traditional pure potassium carbonate in glycerol solvent, resulting in florfenicol intermediates with high purity and high yield.

[0018] 2. The aluminum-magnesium hydrotalcite composite potassium carbonate of the present invention is obtained by sequentially exfoliating with dimethyl sulfoxide, hydrothermal treatment with methanol, and intercalation treatment with hexadecyltrimethylammonium bromide to obtain modified aluminum-magnesium hydrotalcite with a large specific surface area and interlayer spacing. Potassium carbonate is loaded onto the modified aluminum-magnesium hydrotalcite as a carrier. The modified aluminum-magnesium hydrotalcite has a layered structure, and potassium carbonate is uniformly loaded in the interlayer voids and surface of the hydrotalcite, forming uniformly dispersed alkaline active sites. At the same time, the layered structure of the modified aluminum-magnesium hydrotalcite has adsorption and confinement effects, which can enrich benzyl nitrile, increase the local concentration, accelerate the reaction process, and improve the purity and yield of florfenicol intermediate.

[0019] 3. The aluminum-magnesium hydrotalcite composite potassium carbonate of the present invention can prevent loss when dissolved in glycerol solvent. The hydroxyl oxygen atom of glycerol has a lone pair of electrons, which can form a coordinate bond with potassium ions, stripping potassium ions from potassium carbonate crystals, resulting in a decrease in reaction rate. The interlayer confinement effect of modified aluminum-magnesium hydrotalcite can fix potassium carbonate and prevent loss. Attached Figure Description

[0020] Figure 1 This is a process flow diagram for the production of florfenicol intermediates. Detailed Implementation

[0021] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0022] Example 1: Florfenicol intermediate, prepared by the following steps: S1: Add 15g magnesium nitrate, 7.5g aluminum nitrate, 6.4g sodium hydroxide and 1.05g anhydrous sodium carbonate to a reaction vessel, age at 70℃ and 400r / min for 20h, centrifuge at 1000r / min for 10min, filter, wash the precipitate with deionized water until the last wash solution is neutral, and vacuum dry at 60℃ for 1h to obtain aluminum magnesium hydrotalcite.

[0023] S2: Add 10g of aluminum-magnesium hydrotalcite, 200mL of dimethyl sulfoxide and 20mL of deionized water to a reaction vessel, stir at 80℃ and 400r / min for 24h, cool naturally to room temperature, centrifuge at 1000r / min for 10min, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and vacuum dry at 60℃ for 1h to obtain pretreated aluminum-magnesium hydrotalcite.

[0024] S3: Add 8g of pretreated aluminum-magnesium hydrotalcite and 200mL of methanol to a polytetrafluoroethylene hydrothermal reactor and hydrothermally react at 100℃ and 500r / min for 24h. After filtration, wash the filter cake twice with anhydrous ethanol and deionized water, and vacuum dry at 60℃ for 1h to obtain hydrothermal aluminum-magnesium hydrotalcite.

[0025] S4: Add 6g of hydrothermal aluminum-magnesium hydrotalcite, 1g of cetyltrimethylammonium bromide and 200mL of methanol to a polytetrafluoroethylene hydrothermal reactor, and hydrothermally react at 100℃ and 500r / min for 24h. After naturally cooling to room temperature, centrifuge at 10000r / min for 3min, filter, wash the filter cake twice with methanol and deionized water, and vacuum dry at 60℃ for 1h to obtain modified aluminum-magnesium hydrotalcite.

[0026] S5: 5g of modified aluminum-magnesium hydrotalcite and 100mL of 1mol / L potassium carbonate solution were stirred and mixed at 500r / min for 24h, dried under vacuum at 60℃ for 1h, and then placed in a muffle furnace and calcined at 450℃ for 4h to obtain aluminum-magnesium hydrotalcite composite potassium carbonate.

[0027] S6: Add 200 kg D-ester, 480 kg methanol, and 56 kg potassium borohydride to a reduction vessel and reduce for 2 h at 50 °C and 40 r / min. Distill the methanol, then add 168 kg of 98% concentrated hydrochloric acid and deionized water, cool to -5 °C and keep warm for 2 h, centrifuge at 1000 r / min for 10 min, wash the product twice with frozen ethanol to obtain a centrifuged wet product; add 180 kg of the centrifuged wet product to a cyclization vessel, then add 750 kg glycerol, 65 kg aluminum magnesium hydrotalcite composite potassium carbonate, and 135 kg benzyl nitrile, keep warm at 105 °C and 40 r / min for 10 h, cool naturally to room temperature, crystallize with water, centrifuge at 1000 r / min for 10 min, wash the product twice with 266 kg of 50% frozen isopropanol solution, and vacuum dry at 60 °C for 1 h to obtain florfenicol intermediate.

[0028] Example 2: Florfenicol intermediate, prepared by the following steps: S1: Add 16g magnesium nitrate, 8g aluminum nitrate, 6.6g sodium hydroxide and 1.115g anhydrous sodium carbonate to a reaction vessel, age at 72.5℃ and 450r / min for 21h, centrifuge at 1100r / min for 11min, filter, wash the precipitate with deionized water until the last wash is neutral, and vacuum dry at 65℃ for 1.5h to obtain aluminum magnesium hydrotalcite.

[0029] S2: 11g of aluminum-magnesium hydrotalcite, 210mL of dimethyl sulfoxide and 21mL of deionized water were added to a reaction vessel and stirred at 82.5℃ and 450r / min for 25h. After naturally cooling to room temperature, the mixture was centrifuged at 1100r / min for 11min, filtered, and the precipitate was washed three times with deionized water and anhydrous ethanol. The precipitate was then vacuum dried at 65℃ for 1.5h to obtain pretreated aluminum-magnesium hydrotalcite.

[0030] S3: Add 9g of pretreated aluminum-magnesium hydrotalcite and 225mL of methanol to a polytetrafluoroethylene hydrothermal reactor and hydrothermally react at 105℃ and 550r / min for 25h. After filtration, wash the filter cake three times with anhydrous ethanol and deionized water, and vacuum dry at 65℃ for 1.5h to obtain hydrothermal aluminum-magnesium hydrotalcite.

[0031] S4: 6.5g of hydrothermal aluminum-magnesium hydrotalcite, 1.5g of cetyltrimethylammonium bromide and 225mL of methanol were added to a polytetrafluoroethylene hydrothermal reactor and hydrothermally reacted at 105℃ and 550r / min for 25h. After naturally cooling to room temperature, the mixture was centrifuged at 11000r / min for 3.5min, filtered, and the filter cake was washed three times with methanol and deionized water. The mixture was then vacuum dried at 65℃ for 1.5h to obtain modified aluminum-magnesium hydrotalcite.

[0032] S5: 5.5g of modified aluminum-magnesium hydrotalcite and 110mL of 1.1mol / L potassium carbonate solution were stirred and mixed at 550r / min for 25h, dried under vacuum at 65℃ for 1.5h, and then placed in a muffle furnace and calcined at 475℃ for 4.5h to obtain aluminum-magnesium hydrotalcite composite potassium carbonate.

[0033] S6: 200.1kg D-ester, 485 kg of methanol, and 57 kg of potassium borohydride were added to a reduction reactor and reduced at 52.5 °C and 45 r / min for 2.5 h. The methanol was distilled off, and then 169 kg of 98% concentrated hydrochloric acid and 1375 kg of deionized water were added. The mixture was cooled to -5 °C and kept at that temperature for 2.5 h. After centrifugation at 1100 r / min for 11 min, the product was washed three times with 370 kg of refrigerated ethanol to obtain a centrifuged wet product. 185 kg of the centrifuged wet product was added to a cyclization reactor, and then 755 kg of glycerol, 66 kg of aluminum magnesium hydrotalcite composite potassium carbonate, and 136.5 kg of benzyl nitrile were added. The mixture was kept at 107.5 °C and 45 r / min for 11 h and allowed to cool naturally to room temperature. The product was crystallized with water and centrifuged at 1100 r / min for 11 min. The product was washed three times with 268 kg of 55% refrigerated isopropanol solution and dried under vacuum at 65 °C for 1.5 h to obtain the florfenicol intermediate.

[0034] Example 3: Florfenicol intermediate, prepared by the following steps: S1: Add 17g magnesium nitrate, 8.5g aluminum nitrate, 6.8g sodium hydroxide and 1.18g anhydrous sodium carbonate to a reaction vessel, age at 75℃ and 500r / min for 22h, centrifuge at 1200r / min for 12min, filter, wash the precipitate with deionized water until the last wash solution is neutral, and vacuum dry at 70℃ for 2h to obtain aluminum magnesium hydrotalcite.

[0035] S2: Add 12g of aluminum-magnesium hydrotalcite, 220mL of dimethyl sulfoxide and 22mL of deionized water to a reaction vessel, stir at 85℃ and 500r / min for 26h, cool naturally to room temperature, centrifuge at 1200r / min for 12min, filter, wash the precipitate 4 times with deionized water and anhydrous ethanol, and dry under vacuum at 70℃ for 2h to obtain pretreated aluminum-magnesium hydrotalcite.

[0036] S3: Add 10g of pretreated aluminum-magnesium hydrotalcite and 250mL of methanol to a polytetrafluoroethylene hydrothermal reactor and hydrothermally react at 110℃ and 600r / min for 26h. After filtration, wash the filter cake four times with anhydrous ethanol and deionized water and dry it under vacuum at 70℃ for 2h to obtain hydrothermal aluminum-magnesium hydrotalcite.

[0037] S4: 7g of hydrothermal aluminum-magnesium hydrotalcite, 2g of cetyltrimethylammonium bromide and 250mL of methanol were added to a polytetrafluoroethylene hydrothermal reactor and hydrothermally reacted at 110℃ and 600r / min for 26h. After naturally cooling to room temperature, the mixture was centrifuged at 12000r / min for 4min, filtered, and the filter cake was washed 4 times with methanol and deionized water. The mixture was then vacuum dried at 70℃ for 2h to obtain modified aluminum-magnesium hydrotalcite.

[0038] S5: 6g of modified aluminum-magnesium hydrotalcite and 120mL of 1.2mol / L potassium carbonate solution were stirred and mixed at 600r / min for 26h, dried under vacuum at 70℃ for 2h, and then placed in a muffle furnace and calcined at 500℃ for 5h to obtain aluminum-magnesium hydrotalcite composite potassium carbonate.

[0039] S6: 200.2 kg D-ester, 490 kg methanol, and 58 kg potassium borohydride were added to a reduction vessel and reduced for 3 h at 55 °C and 50 r / min. The methanol was distilled, and then 170 kg of 98% concentrated hydrochloric acid and 1380 kg of deionized water were added. The mixture was cooled to -5 °C and kept at that temperature for 3 h. It was then centrifuged at 1200 r / min for 12 min. The product was washed four times with 372 kg of refrigerated ethanol to obtain a centrifuged wet product. 190 kg of the centrifuged wet product was added to a cyclization vessel, and then 760 kg glycerol, 67 kg of aluminum magnesium hydrotalcite composite potassium carbonate, and 138 kg of benzyl nitrile were added. The mixture was kept at 110 °C and 50 r / min for 12 h and allowed to cool naturally to room temperature. The product was crystallized with water and centrifuged at 1200 r / min for 12 min. The product was washed four times with 270 kg of 60% refrigerated isopropanol solution and dried under vacuum at 70 °C for 2 h to obtain the florfenicol intermediate.

[0040] Comparative Example 1: Based on Example 3, the aluminum-magnesium hydrotalcite composite potassium carbonate in step S6 was replaced with commercially available potassium carbonate, while the other steps remained unchanged, to prepare florfenicol intermediate.

[0041] Comparative Example 2: Based on Example 3, the modified aluminum-magnesium hydrotalcite in step S5 was replaced with the aluminum-magnesium hydrotalcite prepared in step S1, while the other steps remained unchanged, and florfenicol intermediate was prepared.

[0042] The purity and molar yield of the florfenicol intermediates prepared in Examples 1-3 and Comparative Examples 1-2 are shown in Table 1: Table 1. Record of purity and molar yield of florfenicol intermediates As can be seen from Table 1, the purity and molar yield of the florfenicol intermediates prepared in Examples 1-3 are significantly better than those in the comparative examples, indicating that the florfenicol intermediates prepared in this invention have high purity and high yield.

[0043] In Comparative Example 1, the aluminum-magnesium hydrotalcite composite potassium carbonate in step S6 was replaced with commercially available potassium carbonate. Pure potassium carbonate is an ionic crystal. The polyhydroxy polar structure of glycerol will break the ionic bonds of potassium carbonate through solvation, causing potassium carbonate to dissolve in glycerol and be carried away in subsequent washing steps. There are not enough effective basic sites in the reaction system, which cannot stably maintain the alkaline environment required for the cyclization reaction, resulting in incomplete reaction. The layered confinement and adsorption of aluminum-magnesium hydrotalcite are lacking, the local concentration of benzyl nitrile in glycerol is low, the reaction rate is slow and the selectivity is poor, and byproducts such as benzyl nitrile polymerization and non-target cyclization are easily generated, which ultimately leads to a significant decrease in the purity of the intermediate.

[0044] In Comparative Example 2, the modified aluminum-magnesium hydrotalcite in step S5 was replaced with the aluminum-magnesium hydrotalcite prepared in step S1. The hydrotalcite was not modified by dimethyl sulfoxide exfoliation, methanol hydrothermal treatment, or hexadecyltrimethylammonium bromide intercalation. The unmodified hydrotalcite had a small specific surface area and narrow interlayer spacing, which could not provide sufficient interlayer voids and surface loading sites for potassium carbonate. Potassium carbonate was prone to agglomerate into large particles, and the alkaline active sites were poorly dispersed. The layered structure of the unmodified hydrotalcite was not sufficiently porous, and it could not effectively adsorb and enrich benzyl nitrile. The contact probability between benzyl nitrile and hydroxyl-containing intermediates decreased, the reaction selectivity decreased, and therefore the purity of the intermediates decreased.

[0045] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A florfenicol intermediate, characterized in that, Prepared by the following steps: Using methanol as solvent and potassium borohydride as reducing agent, the ester group in D-ester is reduced to a hydroxyl group. Then, under the catalysis of aluminum magnesium hydrotalcite composite potassium carbonate, the cyano group of benzyl nitrile undergoes nucleophilic addition with the amino group and then cyclizes with the hydroxyl group to obtain florfenicol intermediate. The structural formula of the florfenicol intermediate is shown in Formula 1: Formula 1.

2. The florfenicol intermediate according to claim 1, characterized in that, The specific preparation steps for the florfenicol intermediate are as follows: D-ester, methanol, and potassium borohydride were added to a reduction vessel and reduced at 50-55℃ and 40-50 r / min for 2-3 h. The methanol was distilled, and then 98 wt% concentrated hydrochloric acid and deionized water were added. The mixture was kept at -5℃ for 2-3 h and centrifuged at 1000-1200 r / min for 10-12 min. The product was washed 2-4 times with refrigerated ethanol to obtain a centrifuged wet product. The centrifuged wet product was added to a cyclization vessel, followed by glycerol, aluminum magnesium hydrotalcite composite potassium carbonate, and benzyl nitrile. The mixture was kept at 105-110℃ and 40-50 r / min for 10-12 h, then naturally cooled to room temperature. The product was crystallized with water, centrifuged at 1000-1200 r / min for 10-12 min, and washed 2-4 times with 50-60 wt% frozen isopropanol solution. The product was then vacuum dried to obtain the florfenicol intermediate.

3. The florfenicol intermediate according to claim 2, characterized in that, The ratio of D-ester, methanol, potassium borohydride, concentrated hydrochloric acid and deionized water is 200-200 kg: 480-490 kg: 56-58 kg: 168-170 kg: 1370-1380 kg.

4. The florfenicol intermediate according to claim 2, characterized in that, The mass ratio of the centrifuged wet product, glycerol, aluminum magnesium hydrotalcite composite potassium carbonate, benzyl nitrile and isopropanol solution is 180-190:750-760:65-67:135-138:266-270.

5. The florfenicol intermediate according to claim 1, characterized in that, The specific preparation steps of the aluminum-magnesium hydrotalcite composite potassium carbonate are as follows: Modified aluminum-magnesium hydrotalcite and potassium carbonate solution with a concentration of 1-1.2 mol / L were stirred and mixed at a ratio of 5-6 g: 100-120 mL at 500-600 r / min for 24-26 h, dried under vacuum at 60-70℃ for 1-2 h, and then calcined in a muffle furnace at 450-500℃ for 4-5 h to obtain aluminum-magnesium hydrotalcite composite potassium carbonate.

6. The florfenicol intermediate according to claim 5, characterized in that, The specific preparation steps of the modified aluminum-magnesium hydrotalcite are as follows: Hydrothermal aluminum-magnesium hydrotalcite, hexadecyltrimethylammonium bromide, and methanol were added to a polytetrafluoroethylene hydrothermal reactor at a ratio of 6-7 g: 1-2 g: 200-250 mL. The reactor was hydrothermally reacted at 100-110 °C and 500-600 r / min for 24-26 h. After natural cooling, the reactor was centrifuged at 10000-12000 r / min for 3-4 min, filtered, washed, and vacuum dried to obtain modified aluminum-magnesium hydrotalcite.

7. The florfenicol intermediate according to claim 6, characterized in that, The specific preparation steps of the hydrothermal aluminum-magnesium hydrotalcite are as follows: Pretreated aluminum-magnesium hydrotalcite and methanol were added to a polytetrafluoroethylene hydrothermal reactor at a ratio of 8-10g:200-250mL. The reactor was hydrothermally reacted at 100-110℃ and 500-600r / min for 24-26h. After filtration, the filter cake was washed 2-4 times with anhydrous ethanol and deionized water and dried under vacuum at 60-70℃ for 1-2h to obtain hydrothermal aluminum-magnesium hydrotalcite.

8. The florfenicol intermediate according to claim 7, characterized in that, The specific preparation steps of the pretreated aluminum-magnesium hydrotalcite are as follows: Aluminum-magnesium hydrotalcite, dimethyl sulfoxide, and deionized water were added to a reaction vessel at a ratio of 10-12 g: 200-220 mL: 20-22 mL. The mixture was stirred at 80-85 °C and 400-500 r / min for 24-26 h, allowed to cool naturally to room temperature, centrifuged at 1000-1200 r / min for 10-12 min, filtered, washed, and vacuum dried to obtain pretreated aluminum-magnesium hydrotalcite.

9. The florfenicol intermediate according to claim 8, characterized in that, The specific preparation steps of the aluminum-magnesium hydrotalcite are as follows: Magnesium nitrate, aluminum nitrate, sodium hydroxide, and anhydrous sodium carbonate were added to a reaction vessel at a mass ratio of 15-17:7.5-8.5:1.05-1.

18. The mixture was aged at 70-75℃ and 400-500 r / min for 20-22 h, centrifuged at 1000-1200 r / min for 10-12 min, filtered, and the precipitate was washed with deionized water until the final wash solution was neutral. The precipitate was then vacuum dried to obtain aluminum magnesium hydrotalcite.

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