Preparation method of all-fluid chloro-oxytetracycline

Abstract

The invention discloses a preparation method of all-fluid chloro-oxytetracycline, and belongs to the technical field of pharmaceutical chemicals. The method comprises the following steps: 1) adding methanol and anhydrous calcium chloride into a reactor, stirring for dissolving, cooling, adding oxytetracycline after cooling to a preset temperature, stirring, adding triethylamine, stirring for dissolving to obtain a solution A, and preserving heat for later use; 2) adding methanol and a chlorination reagent into the reactor, stirring and dissolving to obtain a solution B, and preserving heat for later use; and (3) adding methanol into the reactor, cooling, dropwise adding the solution A and the solution B, continuing cooling reaction after dropwise adding, filtering and washing a filter cake after reaction, and drying the filter cake to obtain the chloro-oxytetracycline. According to the method, the oxytetracycline is completely dissolved for the first time and then is subjected to liquid-liquid reaction, so that the problems of side reaction and incomplete reaction are greatly reduced, the production efficiency is improved, the manpower consumption can be greatly reduced, no solid waste is generated, the post-treatment cost is low, and the recovery is convenient.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a preparation method of all-fluid chloroxytetracycline. Background Art

[0002] Doxycycline hydrochloride, chemical name is 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide hydrochloride hemiethanol hemihydrate, structural formula is:

[0003]

[0004] Doxycycline hydrochloride is a broad-spectrum semi-synthetic tetracycline antibiotic, which is effective against Gram-positive bacteria, Gram-negative bacteria and Chlamydia. It is clinically used for the treatment of respiratory tract infections, biliary tract infections, tonsillitis, lymphadenitis, cellulitis, chronic bronchitis in the elderly, mycoplasma pneumonia, syphilis, gonorrhea, typhus, cholera, relapsing fever, and the prevention of malignant malaria and leptospira. It can also be taken for a short period of time as a preventive medicine for travelers' diarrhea. Chloroxycycline is an important intermediate in the production of doxycycline hydrochloride. It is prepared by chlorination of oxytetracycline and is used to prepare 11α-chloro-6-methoxyoxytetracycline, which is an important intermediate in the production of doxycycline. The preparation methods of chloroxycycline in the prior art mainly include the following:

[0005] (1) "Study on the synthesis of a key intermediate of doxycycline (Chemical Research and Application, 2018, 38(9): 1354-1357)", by adding N-chloroacetanilide in batches to oxytetracycline added with methanol-ammonia solution to obtain chlorinated oxytetracycline. This method is simple and convenient to operate, but chlorination of oxytetracycline is an exothermic reaction and a solid-solid reaction, which results in large local heat release, resulting in an increase in by-products and low yield.

[0006] (2) “A method for preparing chlorinated oxytetracycline (CN106946816A; publication date: 2017.04.12)”, the process steps of which are: using methanol as a solvent, adding oxytetracycline, cooling and adding N-chlorosuccinimide, reacting for one hour, filtering, and drying the obtained solid to obtain chlorinated oxytetracycline. However, the chlorinating agent in this process is N-chlorosuccinimide, which is also a solid feed, and the waste liquid contains excessive N-chlorosuccinimide, which has a high treatment cost.

[0007] (3) “A method for preparing chlorinated oxytetracycline (CN111393319A; publication date: 2020.04.22)”, the process steps of which are: using water as a solvent, adding solid cyanuric acid, and after dissolving, passing chlorine gas into the solution to react to obtain solid monochloroisocyanuric acid, and then using methanol as a solvent, adding oxytetracycline, and then adding solid monochloroisocyanuric acid to react to obtain chlorinated oxytetracycline; however, this process uses chlorine gas, which is highly dangerous, and requires a large amount of solid feed, which consumes a lot of manpower.

[0008] (4) "A method for synthesizing N-chlorooxytetracycline (CN115043751A; publication date: 2022.09.13)", the process steps are as follows: (1) Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add methanol, and cool down; (2) After cooling to -15 to -10°C, add oxytetracycline and stir; (3) First add an auxiliary agent, then add tert-butyl hypochlorite, and keep warm to continue the reaction for 1 to 1.5 hours; wherein the auxiliary agent is dimethylamine, monomethylamine or anhydrous sodium acetate solution, and the amount of tert-butyl hypochlorite added is 1.5 equivalents of oxytetracycline; (4) Filter, rinse the filter cake with cold methanol, and then dry it by rotary evaporation to obtain N-chlorooxytetracycline. However, the tert-butyl hypochlorite used in this process is prone to violent decomposition reaction when exposed to light or overheated, and needs to be stored at low temperature, away from light, and in an inert gas, which is highly dangerous.

[0009] Therefore, the existing preparation methods of chlorinated oxytetracycline cannot form continuous operations, have low production efficiency, usually use solid feeds, require a lot of manpower, and are accompanied by the generation of solid waste, which increases the difficulty of recycling, or use toxic chlorinating agents, which are more dangerous. Summary of the invention

[0010] The technical problem solved by the present invention is to provide a method for preparing a fully fluid chlorinated oxytetracycline.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing a fully fluid chlorinated oxytetracycline comprises the following steps:

[0013] 1) Preparation of Solution A

[0014] Add methanol and anhydrous calcium chloride to the reactor, stir to dissolve and cool down, add oxytetracycline after cooling to a predetermined temperature, stir, add triethylamine and stir to dissolve to obtain solution A, and keep warm for later use;

[0015] 2) Preparation of Solution B

[0016] Add methanol and chlorination reagent into the reactor, stir and dissolve to obtain solution B, and keep warm for later use;

[0017] 3) Preparation of chloroxytetracycline

[0018] Methanol was added to the reactor, and solution A and solution B were added dropwise after cooling. After the addition was completed, the temperature was continued to be lowered for reaction. After the reaction was completed, the reaction was filtered, the filter cake was rinsed with cold methanol, and the filter cake was dried to obtain chlortetracycline.

[0019] In the step 1), the mass ratio of anhydrous calcium chloride to oxytetracycline is 0.04-0.06:1.

[0020] In the step 1), the molar ratio of triethylamine to oxytetracycline is 0.25-0.35:1.

[0021] The volume mass ratio of the total content of methanol to oxytetracycline in step 1) and step 2) is 12 to 14: 1. The chlorination reagent in step 2) is chloroacetanilide.

[0022] In the step 2), the molar ratio of chloroacetanilide to oxytetracycline is 1.05-1.1:1.

[0023] The step 3) is to simultaneously drop solution A and solution B into the reactor at a uniform speed.

[0024] In step 3), the dropwise addition time of solution A and solution B is the same, 60 to 70 minutes.

[0025] In step 3), the filter cake is rinsed with cold methanol and dried in vacuum at 60°C.

[0026] The reaction temperature in steps 1) to 3) is -12 to -8°C.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] (1) The present invention is the first to completely dissolve oxytetracycline and then conduct a liquid-liquid reaction, which greatly reduces the occurrence of side reactions and the problem of incomplete reactions.

[0029] (2) The present invention uses oxytetracycline solution and chlorination reagent solution to drip each other at a uniform speed and low temperature, which provides a continuous and stable weak alkaline environment for the reaction, which is conducive to the reaction.

[0030] (3) The present invention truly achieves the full-fluid preparation of chlortetracycline, improves production efficiency, greatly saves manpower consumption, and does not generate solid waste, has low post-processing costs, and is easy to recycle. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The high performance liquid chromatogram of chloroxytetracycline prepared in Example 1 of the present invention;

[0032] Figure 2 The high performance liquid chromatogram of chloroxytetracycline prepared in Example 2 of the present invention;

[0033] Figure 3 This is a high performance liquid chromatogram of chlortetracycline prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0034] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0035] Example 1

[0036] (1) Preparation of Solution A

[0037] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 150 mL of methanol and 1 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline and stir for 5 min, add 1.2 g of triethylamine and stir to dissolve, and keep warm at -10°C for later use.

[0038] (2) Preparation of Solution B

[0039] Place a three-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 100 mL of methanol and 7.2 g of chloroacetanilide, stir to dissolve, and cool to -10°C for later use.

[0040] (3) Preparation of chlortetracycline

[0041] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly drop solution A and solution B into the four-necked flask. The dropwise addition time is the same, 60 to 70 minutes. After the dropwise addition is completed, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 19.5 g of chloroxytetracycline, with a molar yield of 97.81%, a HPLC purity of 96.26%, and 0.41% oxytetracycline residue.

[0042] Example 2

[0043] (1) Solution A was prepared in the same manner as in Example 1.

[0044] (2) Preparation of Solution B

[0045] Place a three-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 100 mL of methanol and 6.8 g of chloroacetanilide, stir to dissolve, and cool to -10°C for later use.

[0046] (3) Preparation of chlortetracycline

[0047] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 18.9 g of chloroxytetracycline, with a molar yield of 94.80%, a HPLC purity of 94.08%, and 2.64% oxytetracycline residue.

[0048] Example 3

[0049] (1) Solution A was prepared in the same manner as in Example 1.

[0050] (2) Preparation of Solution B

[0051] Place a three-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 100 mL of methanol and 7.5 g of chloroacetanilide, stir to dissolve, and cool to -10°C for later use.

[0052] (3) Preparation of chlortetracycline

[0053] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly drop solution A and solution B into the four-necked flask. The dropwise addition time is the same, 60 to 70 minutes. After the dropwise addition is completed, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 19.3 g of chloroxytetracycline, with a molar yield of 96.81%, a HPLC purity of 96.45%, and a residual oxytetracycline of 0.33%.

[0054] Example 4

[0055] (1) Solution A was prepared in the same manner as in Example 1.

[0056] (2) Preparation of Solution B

[0057] Place a three-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 100 mL of methanol and 7.9 g of chloroacetanilide, stir to dissolve, and cool to -10°C for later use.

[0058] (3) Preparation of chlortetracycline

[0059] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 19.1 g of chloroxytetracycline, with a molar yield of 95.81%, a HPLC purity of 96.89%, and 0.25% oxytetracycline residue.

[0060] Example 5

[0061] (1) Solution A was prepared in the same manner as in Example 1.

[0062] (2) Preparation of Solution B

[0063] Place a three-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 100 mL of methanol and 8.2 g of chloroacetanilide, stir to dissolve, and cool to -10°C for later use.

[0064] (3) Preparation of chlortetracycline

[0065] A four-necked flask equipped with a thermometer and a stirrer was placed in a refrigerator, 10 mL of methanol was added, and after cooling to -10°C, solution A and solution B were uniformly added dropwise to the four-necked flask at the same speed, and the addition time of both was the same, 60 to 70 minutes. After the addition was completed, the mixture was kept at -10°C for 30 minutes. After the reaction was completed, the mixture was filtered, the filter cake was rinsed with cold methanol, and the filter cake was dried in a vacuum oven at 60°C to finally obtain 18.7 g of chloroxytetracycline, with a molar yield of 93.80%, a HPLC purity of 96.92%, and a residual oxytetracycline of 0.16%.

[0066] As can be seen from Examples 1-5, the amount of chloroacetanilide used not only affects the purity of the product, but also affects the yield. When the amount is too small, the oxytetracycline residue is high and the product purity is low; when the amount is gradually increased, the oxytetracycline residue is less and less, and the product purity is also improving, but with the increase in the amount, the product yield is also gradually decreasing.

[0067] Example 6

[0068] (1) Solution A was prepared in the same manner as in Example 1.

[0069] (2) Solution B was prepared in the same manner as in Example 1.

[0070] (3) Preparation of chlortetracycline

[0071] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -5°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -5°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 18.8 g of chloroxytetracycline, with a molar yield of 94.30%, a HPLC purity of 94.26%, and 1.82% of oxytetracycline residue.

[0072] The difference between this embodiment and embodiment 1 is that the reaction temperature is -5°C, and the final yield and solid purity are both reduced.

[0073] Example 7

[0074] (1) Preparation of Solution A

[0075] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 150 mL of methanol and 1 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline and stir for 5 min, add 0.6 g of triethylamine and stir to dissolve, and keep warm at -10°C for later use.

[0076] (2) Solution B was prepared in the same manner as in Example 1.

[0077] (3) Preparation of chlortetracycline

[0078] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 17.6 g of chloroxytetracycline, with a molar yield of 88.28%, a HPLC purity of 81.54%, and 15.58% of oxytetracycline residue.

[0079] The difference between this embodiment and embodiment 1 is that the amount of triethylamine used is halved, the final yield and purity are greatly reduced, the residual oxytetracycline is high, and the reaction is incomplete.

[0080] Example 8

[0081] (1) Preparation of Solution A

[0082] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 150 mL of methanol and 1 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline and stir for 5 min, add 2.4 g of triethylamine and stir to dissolve, and keep warm at -10°C for later use.

[0083] (2) Solution B was prepared in the same manner as in Example 1

[0084] (3) Preparation of chlortetracycline

[0085] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 15.4 g of chloroxytetracycline, with a molar yield of 77.25%, a HPLC purity of 96.32%, and 0.23% oxytetracycline residue.

[0086] The difference between this embodiment and embodiment 1 is that the amount of triethylamine used is doubled, and the final purity and oxytetracycline residue are normal, but the yield is severely reduced, which may be due to the excessive alkalinity of the system leading to the degradation of oxytetracycline.

[0087] Example 9

[0088] (1) Preparation of Solution A

[0089] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 100 mL of methanol, 1 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline, stir for 5 min, add 2.4 g of triethylamine, stir to dissolve, and keep warm at -10°C for later use.

[0090] (2) Solution B was prepared in the same manner as in Example 1.

[0091] (3) Preparation of chlortetracycline

[0092] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 19.6 g of chloroxytetracycline, with a molar yield of 98.31%, a HPLC purity of 94.89%, and 0.98% oxytetracycline residue.

[0093] The difference between this embodiment and embodiment 1 is that the amount of methanol used is reduced, the final yield is slightly improved, but the purity is reduced and the oxytetracycline residue is increased.

[0094] Example 10

[0095] (1) Preparation of Solution A

[0096] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 200 mL of methanol and 1 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline and stir for 5 min, add 2.4 g of triethylamine and stir to dissolve, and keep warm at -10°C for later use.

[0097] (2) Solution B was prepared in the same manner as in Example 1.

[0098] (3) Preparation of chlortetracycline

[0099] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly drop solution A and solution B into the four-necked flask. The dropwise addition time is the same, 60 to 70 minutes. After the dropwise addition is completed, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 19.3 g of chloroxytetracycline, with a molar yield of 96.31%, a HPLC purity of 96.34%, and 0.42% oxytetracycline residue.

[0100] The difference between this embodiment and embodiment 1 is that the final yield is slightly reduced by increasing the amount of methanol used.

[0101] Embodiment 11

[0102] (1) Preparation of Solution A

[0103] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 210 mL of methanol, 0.5 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline, stir for 5 min, add 1.2 g of triethylamine, stir to dissolve, and keep warm at -10°C for later use.

[0104] (2) Solution B was prepared in the same manner as in Example 1.

[0105] (3) Preparation of chlortetracycline

[0106] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 18.9 g of chloroxytetracycline, with a molar yield of 94.80%, a HPLC purity of 96.11%, and 0.39% oxytetracycline residue.

[0107] The difference between this embodiment and embodiment 1 is that after the anhydrous calcium chloride is halved, oxytetracycline cannot be completely dissolved. It can be dissolved by increasing the amount of methanol, with little effect on the final purity, but the yield decreases significantly.

[0108] Example 12

[0109] (1) Preparation of Solution A

[0110] Place a three-necked flask equipped with a thermometer and a stirrer in a freezer, add 150 mL of methanol and 2 g of anhydrous calcium chloride, stir to dissolve and cool to -10°C, then add 20 g of oxytetracycline and stir for 5 min, add 1.2 g of triethylamine and stir to dissolve, and keep warm at -10°C for later use.

[0111] (2) Solution B was prepared in the same manner as in Example 1.

[0112] (3) Preparation of chlortetracycline

[0113] Place a four-necked flask equipped with a thermometer and a stirrer in a refrigerator, add 10 mL of methanol, cool to -10°C, and then uniformly add solution A and solution B to the four-necked flask. The addition time of both is the same, 60 to 70 minutes. After the addition is complete, continue to keep warm at -10°C for 30 minutes. After the reaction is completed, filter, rinse the filter cake with cold methanol, and dry the filter cake in a vacuum oven at 60°C to finally obtain 18.1 g of chloroxytetracycline, with a molar yield of 90.79%, a HPLC purity of 95.25%, and 0.36% oxytetracycline residue.

[0114] The difference between this embodiment and embodiment 1 is that after doubling the amount of anhydrous calcium chloride, the final purity decreases slightly and the yield decreases significantly.

[0115] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a fully fluid chlorinated oxytetracycline, characterized in that: The following steps are involved: 1) Preparation of Solution A Add methanol and anhydrous calcium chloride into the reactor, stir to dissolve and cool down, add oxytetracycline after cooling to a predetermined temperature, stir, add triethylamine and stir to dissolve to obtain solution A, and keep warm for later use; 2) Preparation of Solution B Add methanol and chlorination reagent into the reactor, stir and dissolve to obtain solution B, and keep warm for later use; 3) Preparation of chloroxytetracycline Methanol was added to the reactor, and solution A and solution B were added dropwise after the temperature was lowered. After the addition was completed, the temperature was continued to be lowered for reaction. After the reaction was completed, the reaction was filtered, the filter cake was washed, and the filter cake was dried to obtain chlortetracycline.

2. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: In the step 1), the mass ratio of anhydrous calcium chloride to oxytetracycline is 0.04-0.06:

1.

3. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: In the step 1), the molar ratio of triethylamine to oxytetracycline is 0.25-0.35:

1.

4. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: The volume mass ratio of the total content of methanol to oxytetracycline in step 1) and step 2) is 12 to 14:

1.

5. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: In the step 2), the chlorination reagent is chloroacetanilide.

6. The method for preparing the all-fluid chloroxytetracycline according to claim 5, characterized in that: In the step 2), the molar ratio of chloroacetanilide to oxytetracycline is 1.05-1.1:

1.

7. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: The step 3) is to simultaneously drop solution A and solution B into the reactor at a uniform speed.

8. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: In step 3), the dropwise addition time of solution A and solution B is the same, 60 to 70 minutes.

9. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: In step 3), the filter cake is rinsed with cold methanol and dried in vacuum at 60°C.

10. The method for preparing the all-fluid chloroxytetracycline according to claim 1, characterized in that: The reaction temperature in steps 1) to 3) is -12 to -8°C.

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