CN115594605A - Preparation method of doxycycline intermediate - Google Patents
Preparation method of doxycycline intermediate Download PDFInfo
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Abstract
The invention relates to the technical field of veterinary drugs, in particular to a preparation method of a doxycycline intermediate, which comprises the following steps of (1) preparing a chlorinating agent: dissolving amide compounds in water, adding sodium bicarbonate, stirring, adding sodium hypochlorite solution, adding dichloromethane, stirring, standing for layering, and collecting the lower layer to obtain solution containing chlorinated agent; (2) preparation of doxycycline intermediate: taking oxytetracycline, adding methanol, stirring uniformly, cooling, adding a sodium acetate solution and a chlorinating agent, reacting under heat preservation, filtering and drying to obtain an oxytetracycline chlorination product, namely a doxycycline intermediate. The method improves the yield of the target product, reduces the production cost and the pollution to the environment, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of veterinary drugs, and in particular relates to a preparation method of a doxycycline intermediate.
Background
The oxytetracycline is a key intermediate for producing doxycycline, the doxycycline is a semisynthetic tetracycline antibiotic obtained by deoxidizing the oxytetracycline at the 6 alpha-position, is mainly used for upper respiratory tract infection, tonsillitis, biliary tract infection, lymphadenitis, cellulitis, senile chronic bronchitis and the like caused by sensitive gram-positive cocci and gram-negative bacilli, and is also used for typhus, tsutsugamushi disease, mycoplasma pneumonia and the like. It can also be used for treating cholera, and preventing malignant malaria and treponema pallidum infection.
At present, the production process of the chloro-oxytetracycline generally takes acetanilide or succinimide as raw materials, dechlorination is carried out by using chlorine gas or sodium hypochlorite and trichloroisocyanuric acid to obtain a chlorinating agent, and then the chlorinating agent is used for chlorinating the oxytetracycline to obtain an intermediate of the doxycycline. However, raw materials such as acetanilide and succinimide have high melting point and boiling point, so that the raw materials are difficult to recover, the subsequent solid waste treatment is troublesome, the process cost is increased, and the product yield needs to be improved. Tert-butyl hypochlorite is synthesized by using tert-butyl alcohol, sodium hypochlorite and glacial acetic acid as a chlorinating agent, but the tert-butyl hypochlorite is poor in stability, easy to explode and not beneficial to transportation, industrial risk is high in actual production and application, and the chlorinating agent with over-strong oxidizability has a destructive effect on oxytetracycline. Therefore, in order to solve the above problems, it is necessary to develop a process for preparing a doxycycline intermediate.
Disclosure of Invention
The invention aims to: aiming at the defects in the prior art, the preparation method of the doxycycline intermediate is provided, the product yield can be improved, the production cost and the pollution to the environment are reduced, and the method is suitable for industrial production.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a preparation method of a doxycycline intermediate, comprising the following steps:
(1) Preparation of chlorinated agent: dissolving an amide compound in water, adding sodium bicarbonate according to the molar ratio of 1.2-1.5 to the amide compound to 1, uniformly stirring, adding a sodium hypochlorite solution according to the molar ratio of 1-1.1 to the amide compound to 1 within 30-40min, controlling the reaction temperature to be 0-10 ℃, carrying out heat preservation reaction for 8-15min, adding dichloromethane, continuing stirring, standing for layering, and collecting a lower layer, namely a solution containing a chlorinating agent; wherein the amide compound is N-methylformamide, N-methylacetamide, N-ethylformamide or N-ethylacetamide;
(2) Preparation of doxycycline intermediate: taking oxytetracycline, adding methanol, stirring and mixing uniformly, cooling to-15-8 ℃, adding a sodium acetate solution according to the molar ratio of the sodium acetate to the oxytetracycline being 0.2-0.5.
As an improved technical scheme, in the step (1), the amide compound is N-ethylformamide, sodium bicarbonate is added according to the molar ratio of the amide compound to the N-ethylformamide of 1.35.
As an improved technical scheme, the reaction temperature in the step (1) is controlled to be 0 ℃, and the reaction is carried out for 10min under the condition of heat preservation.
As an improved technical scheme, in the step (2), a chlorinating agent solution is added according to the molar ratio of the chlorinating agent to the oxytetracycline of 1.1.
As an improved technical scheme, in the step (2), a sodium acetate solution is added according to the molar ratio of sodium acetate to oxytetracycline of 0.4.
As an improved technical scheme, the temperature of the heat preservation reaction in the step (2) is-10 ℃.
By adopting the technical scheme, compared with the prior art, the invention has the following advantages:
the invention takes any one of N-methylformamide, N-methylacetamide, N-ethylformamide or N-ethylacetamide as a reaction raw material, compared with the traditional acetanilide and succinimide, the invention has low melting point and lower boiling point, is in a liquid state at normal temperature and can realize liquid feeding; adding sodium hypochlorite, reacting at 0-10 ℃ by using sodium bicarbonate as an alkali binding agent, and extracting by using dichloromethane to obtain a chlorinating agent; methanol is used as a solvent, sodium acetate is used as an auxiliary agent, and a chlorinating agent and the oxytetracycline perform chlorination reaction at a temperature of between 15 ℃ below zero and 8 ℃ below zero to obtain an oxytetracycline chlorination product (doxycycline intermediate). The raw materials for preparing the chlorinating agent are liquid materials, so that reduced pressure distillation and recovery can be realized, and compared with the conventional process, the production cost can be saved, and the generation of solid wastes and residues can be reduced; the preparation method can greatly improve the yield of the oxytetracycline chlorinated product and is suitable for industrial production.
Drawings
FIG. 1 is a mass spectrum of the chlorinating agent of example 13;
FIG. 2 is the HPLC analysis of oxytetracycline chloride in example 13.
Detailed Description
The present invention will be described in further detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Example 1
(1) Putting 480.02g of purified water into a 2L four-mouth bottle, adding 51.26g (AR, 99%) of sodium bicarbonate, then adding 30.06g of N-methylformamide (AR, 99%), stirring to fully mix the purified water, lowering the temperature to 10 ℃, starting to dropwise add 290.31g of sodium hypochlorite solution into the purified water, keeping the temperature for reaction for 30min, after the dropwise addition is finished, adding 270.04g of dichloromethane into the mixture, stirring for 8min, extracting and layering, adding 270.01g of dichloromethane into a water layer again to perform secondary extraction, mixing chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, wherein the mass of the mixed chlorinated agent is 552.18g, the detection content of the mixed chlorinated agent is 7.49%, the mass of the chlorinated agent is 41.36g, and calculating the product yield to be 87.79%.
(2) Adding 140.07g of methanol into a 500mL four-mouth bottle, adding 20.06g of oxytetracycline, cooling to-15 ℃, dissolving 0.67g of sodium acetate with 40.06g of methanol to serve as an auxiliary agent, taking 50.43g of dichloromethane solution of a chlorinating agent, simultaneously dropwise adding the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dropwise adding, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 21.98g of oxytetracycline chlorinated product with the purity of 87.23% and the yield of 95.92%.
Example 2
(1) Putting 480.06g of purified water into a 2L four-mouth bottle, adding 41.38g (AR, 99%) of sodium bicarbonate, then adding 29.99g of N-ethylformamide (AR, 99%), stirring to fully mix, dropping 234.65g of sodium hypochlorite solution into the bottle when the temperature is reduced to 10 ℃, the dropping time is 35min, keeping the temperature for reaction for 10min after the dropping is finished, adding 270.06g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, extracting and layering, adding 270.14g of dichloromethane into a water layer again for secondary extraction, mixing the chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, the mass of the mixed chlorinated agent is 552.89g, the detection content of the mixed chlorinated agent is 6.73%, the mass of the chlorinated agent is 37.21g, and calculating the product yield to be 85.19%.
(2) Adding 140.03g of methanol into a 500mL four-mouth bottle, adding 20.03g of oxytetracycline, cooling to-15 ℃, dissolving 0.65g of sodium acetate with 39.98g of methanol to serve as an auxiliary agent, taking 64.44g of dichloromethane solution of a chlorinating agent, dropwise adding the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 50min after dropwise adding, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 23.27 g of oxytetracycline chlorinated product, wherein the purity is 82.06%, and the yield is 95.67%.
Example 3
(1) Putting 480.01g of purified water into a 2L four-mouth bottle, adding 41.34g (AR, 99%) of sodium bicarbonate, then adding 29.96g of N-methylacetamide (AR, 99%), stirring to fully mix the purified water, cooling to 10 ℃, starting to dropwise add 234.68g of sodium hypochlorite solution into the purified water, keeping the temperature for reaction for 40min, keeping the temperature for 15min after the dropwise adding is finished, adding 270.02g of dichloromethane into the reaction, stirring for 10min after the reaction is finished, extracting and layering, adding 270.01g of dichloromethane into a water layer again for secondary extraction, mixing chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, wherein the mass of the mixed chlorinated agent is 545.58g, the detection content of the mixed chlorinated agent is 6.79%, the mass of the chlorinated agent is 37.04g, and calculating the product yield to be 84.89%.
(2) Adding 139.97g of methanol into a 500mL four-mouth bottle, adding 20.05g of oxytetracycline, cooling to-15 ℃, dissolving 0.67g of sodium acetate with 39.97g of methanol to serve as an auxiliary agent, adding 63.93g of dichloromethane solution of a chlorinating agent, simultaneously adding dropwise the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 40min after dropwise addition, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.41g of oxytetracycline chlorinated product, wherein the purity is 84.87%, and the yield is 95.20%.
Example 4
(1) Adding 479.96g of purified water into a 2L four-mouth bottle, adding 34.71g (AR, 99%) of sodium bicarbonate, then adding 30.03g of N-ethylacetamide (AR, 99%), stirring to fully mix, dropping 196.86g of sodium hypochlorite solution into the bottle when the temperature is reduced to 10 ℃, keeping the temperature for reaction for 10min after the dropping is finished, adding 269.97g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, extracting and layering, adding 270g of dichloromethane into a water layer again for secondary extraction, mixing the chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, wherein the mass is 553.80g after mixing, the detection content is 6.21% after mixing, the mass of the chlorinated agent is 34.39g, and the product yield is calculated to be 82.91%.
(2) Adding 140g of methanol into a 500mL four-mouth bottle, adding 19.99g of oxytetracycline, cooling to-15 ℃, dissolving 0.66g of sodium acetate with 40.02g of methanol to serve as an auxiliary agent, taking 78.79g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.79g of oxytetracycline chlorination product with the purity of 83.52% and the yield of 95.56%.
Example 5
(1) Putting 480.03g of purified water into a 2L four-mouth bottle, adding 64.02g (AR, 99%) of sodium bicarbonate, then adding 30.06g of N-methylformamide (AR, 99%), stirring to fully mix the purified water, when the temperature is reduced to 10 ℃, beginning to dropwise add 290.34g of sodium hypochlorite solution into the purified water, adding the sodium hypochlorite solution for 30min, keeping the temperature for reaction for 10min after the dropwise adding is finished, adding 269.95g of dichloromethane into the mixture after the reaction is finished, stirring for 10min, extracting and layering, adding 270.03g of dichloromethane into a water layer again for secondary extraction, mixing chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, wherein the mass of the mixed chlorinated agent is 549.54g, the detection content of the mixed chlorinated agent is 7.27%, the mass of the chlorinated agent is 39.95g, and calculating the product yield to be 84.80%.
(2) 139.99g of methanol and 20.04g of oxytetracycline are added into a 500mL four-mouth bottle, the temperature is reduced to-15 ℃, 0.68g of sodium acetate is taken and dissolved by 40.01g of methanol to be taken as an auxiliary agent, 57.09g of dichloromethane solution of a chlorinating agent is taken, the auxiliary agent and the dichloromethane solution of the chlorinating agent are simultaneously dripped for 30min, the dripping is finished for 1h, the reaction is filtered after the reaction is finished, and the reaction is dried in vacuum at 40 ℃ for 3h to obtain 23.76g of oxytetracycline chlorination product with the purity of 81.36% and the yield of 96.81%.
Example 6
(1) Putting 480.16g of purified water into a 2L four-mouth bottle, adding 57.65g (AR, 99%) of sodium bicarbonate, then adding 30.14g of N-methylformamide (AR, 99%), stirring to fully mix, lowering the temperature to 10 ℃, starting to dropwise add 290.36g of sodium hypochlorite solution into the bottle, dropwise adding for 30min, carrying out heat preservation reaction for 10min after dropwise adding, adding 270.15g of dichloromethane to stir for 10min after the reaction is finished, carrying out extraction and layering, adding 270.08g of dichloromethane into a water layer again to carry out secondary extraction, mixing chlorinated agent solutions obtained by two extractions, mixing the chlorinated agent solutions, the mass of the mixed chlorinated agent is 557.36g, the detection content of the mixed chlorinated agent is 7.58%, the mass of the chlorinated agent is 42.25g, and the calculated product yield is 89.44%.
(2) Adding 139.97g of methanol into a 500mL four-mouth bottle, adding 20.01g of oxytetracycline, cooling to-15 ℃, dissolving 0.67g of sodium acetate with 40.03g of methanol to serve as an auxiliary agent, taking 64.62g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the chlorinating agent solution for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 23.44g of oxytetracycline chlorinated product, wherein the purity is 82.23%, and the yield is 96.67%.
Example 7
(1) Adding 479.99g of purified water into a 2L four-mouth bottle, adding 57.69g (AR, 99%) of sodium bicarbonate, then adding 30g of N-methylformamide (AR, 99%), stirring to fully mix, dropping 263.94g of sodium hypochlorite solution into the bottle when the temperature is reduced to 10 ℃, keeping the temperature for reaction for 10min after the dropping is finished, adding 270.1g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, extracting and layering, adding 270.01g of dichloromethane into a water layer again for secondary extraction, mixing the chlorinated agents obtained by the two extractions, mixing the chlorinated agents with the mass of 561.82g after mixing, detecting the content of 7.02% after mixing, and calculating the product yield of 83.89%.
(2) Adding 140.10g of methanol into a 500mL four-mouth bottle, adding 20.03g of oxytetracycline, cooling to-15 ℃, dissolving 1.67g of sodium acetate with 40.01g of methanol to serve as an auxiliary agent, taking 59.1g of dichloromethane solution of a chlorinating agent, simultaneously dropwise adding the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dropwise adding, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.81g of oxytetracycline chlorination product with the purity of 84.36% and the yield of 96.41%.
Example 8
(1) Exactly the same as in step (1) of example 6.
(2) Adding 140.18g of methanol into a 500mL four-mouth bottle, adding 20.12g of oxytetracycline, cooling to-8 ℃, dissolving 1.32g of sodium acetate with 40.15g of methanol to serve as an auxiliary agent, taking 54.98g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the chlorinating agent for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.66g of oxytetracycline chlorination product with the purity of 85.78% and the yield of 96.95%.
Example 9
(1) Adding 479.93g of purified water into a 2L four-mouth bottle, adding 57.59g (AR, 99%) of sodium bicarbonate, then adding 30.05g of N-methylformamide (AR, 99%), stirring to fully mix, dropping 290.04g of sodium hypochlorite solution into the bottle when the temperature is reduced to 5 ℃, keeping the temperature for reaction for 10min after dropping, adding 270.37g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, extracting and layering, adding 270.16g of dichloromethane into a water layer again for secondary extraction, mixing the chloro-substituted agent solutions obtained by two extractions, mixing the chloro-substituted agent solutions, wherein the mass of the mixed chloro-substituted agent solution is 548.79g, the detection content of the mixed chloro-substituted agent is 8.2%, the mass of the chloro-substituted agent is 45g, and calculating the product yield to be 95.55%.
(2) Adding 140.06g of methanol into a 500mL four-mouth bottle, adding 19.98g of oxytetracycline, cooling to-8 ℃, dissolving 1.33g of sodium acetate with 40.01g of methanol to serve as an auxiliary agent, dissolving 50.47g of dichloromethane solution of a chlorinating agent, simultaneously dropwise adding the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dropwise adding, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.62g of oxytetracycline chlorinated product with the purity of 85.62% and the yield of 97.28%.
Example 10
(1) Putting 480.02g of purified water into a 2L four-mouth bottle, adding 57.42g (AR, 99%) of sodium bicarbonate, then adding 30g of N-methylformamide (AR, 99%), stirring to fully mix, waiting for the temperature to be reduced to 0 ℃, beginning to dropwise add 290.18g of sodium hypochlorite solution into the bottle, wherein the dropwise adding time is 30min, after the dropwise adding is finished, carrying out heat preservation reaction for 10min, adding 270.09g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, carrying out extraction and layering, adding 270.05g of dichloromethane into a water layer again for secondary extraction, mixing chlorinated reagents obtained by the two-time extraction, wherein the mass of the mixed chlorinated reagents is 554.83g, the detection content of the mixed chlorinated reagents is 8.24%, the mass of the chlorinated reagents is 45.72g, and the product yield is 97.24%.
(2) Adding 140.11g of methanol into a 500mL four-mouth bottle, adding 20.05g of oxytetracycline, cooling to-10 ℃, dissolving 1.34g of sodium acetate with 39.97g of methanol to serve as an auxiliary agent, taking 50.40g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.97g of oxytetracycline chlorination product with the purity of 85.45% and the yield of 98.24%.
Example 11
(1) Putting 480.03g of purified water into a 2L four-mouth bottle, adding 57.61g (AR, 99%) of sodium bicarbonate, then adding 29.96g of N-methylformamide (AR, 99%), stirring to fully mix the purified water, when the temperature is reduced to 0 ℃, beginning to dropwise add 277.14g of sodium hypochlorite solution into the purified water for 30min, keeping the temperature for reaction for 10min after the dropwise addition is finished, adding 270.14g of dichloromethane into the water layer after the reaction is finished, stirring for 10min, extracting and layering, adding 270.21g of dichloromethane into the water layer again for secondary extraction, mixing chlorinated agent solutions obtained by the two extractions, wherein the mass of the mixed chlorinated agent solutions is 559.74g, the detection content of the mixed chlorinated agent is 8.08%, the mass of the chlorinated agent is 45.23g, and the calculated product yield is 96.33%.
(2) Adding 140.03g of methanol into a 500mL four-mouth bottle, adding 20.11g of oxytetracycline, cooling to-10 ℃, dissolving 1.33g of sodium acetate with 40.05g of methanol to serve as an auxiliary agent, adding 51.55g of dichloromethane solution of a chlorinating agent, simultaneously adding dropwise the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dropwise addition, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 23.22g of oxytetracycline chlorination product, wherein the purity is 84.14%, and the yield is 97.50%.
Example 12
(1) Putting 480.05g of purified water into a 2L four-mouth bottle, putting 57.54g (AR, 99%) of sodium bicarbonate, then putting 30.02g of N-methylformamide (AR, 99%), stirring to fully mix the purified water, when the temperature is reduced to 0 ℃, beginning to dropwise add 283.72g of sodium hypochlorite solution into the purified water, adding the sodium hypochlorite solution for 30min, keeping the temperature for reaction for 10min after the dropwise adding is finished, adding 270.11g of dichloromethane into the dichloromethane after the reaction is finished, stirring for 10min, extracting and layering, putting 270.14g of dichloromethane into a water layer again for secondary extraction, mixing chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, wherein the mass of the mixed chlorinated agent is 564.86g, the detection content of the mixed chlorinated agent is 8.15%, the mass of the chlorinated agent is 46.04g, and calculating the product yield to be 97.85%.
(2) Adding 140.10g of methanol into a 500mL four-mouth bottle, adding 20.06g of oxytetracycline, cooling to-10 ℃, dissolving 1.32g of sodium acetate with 40.02g of methanol to serve as an auxiliary agent, taking 50.98g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the chlorinating agent for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.28g of oxytetracycline chlorination product with the purity of 88.58% and the yield of 98.73%.
Example 13
Putting 480.12g of purified water into a 2L four-mouth bottle, adding 46.55g (AR, 99%) of sodium bicarbonate, then adding 30.04g of N-ethylformamide (AR, 99%), stirring to fully mix, dropping 229.65g of sodium hypochlorite solution into the bottle when the temperature is reduced to 0 ℃, the dropping time is 30min, carrying out heat preservation reaction for 10min after the dropping is finished, adding 270.10g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, carrying out extraction and layering, adding 270.04g of dichloromethane into a water layer again for secondary extraction, mixing the chloro-forming agent solutions obtained by the two extractions, mixing the chloro-forming agent solutions, the mass of the mixed chloro-forming agent is 544.55g, the detection content of the mixed chloro-forming agent is 8.01%, the mass of the chloro-forming agent is 43.62g, and calculating the product yield to be 99.69%.
Adding 140.05g of methanol into a 500mL four-mouth bottle, adding 20.09g of oxytetracycline, cooling to-10 ℃, dissolving 1.34g of sodium acetate with 40.05g of methanol to serve as an auxiliary agent, taking 59.73g of dichloromethane solution of a chlorinating agent, simultaneously dropwise adding the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dropwise adding, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.85g of oxytetracycline chlorinated product with the purity of 86.76% and the yield of 99.03%.
Example 14
Putting 480.15g of purified water into a 2L four-mouth bottle, adding 46.56g (AR, 99%) of sodium bicarbonate, then adding 30.03g of N-methylacetamide (AR, 99%), stirring to fully mix, dropping 229.43g of sodium hypochlorite solution into the bottle when the temperature is reduced to 0 ℃, the dropping time is 30min, carrying out heat preservation reaction for 10min after the dropping is finished, adding 270.14g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, carrying out extraction and layering, adding 270.01g of dichloromethane into a water layer again for secondary extraction, mixing the chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, the mass of the mixed chlorinated agent is 552.35g, the detection content of the mixed chlorinated agent is 7.73%, the mass of the chlorinated agent is 42.7g, and calculating the product yield to be 97.62%.
139.98g of methanol and 20.06g of oxytetracycline are added into a 500mL four-mouth bottle, the temperature is reduced to-10 ℃, 1.33g of sodium acetate is taken and dissolved by 40.03g of methanol to be taken as an auxiliary agent, 61.81g of dichloromethane solution of a chlorinating agent is taken, the auxiliary agent and the dichloromethane solution of the chlorinating agent are simultaneously dripped for 30min, the dripping is finished for 1h, the reaction is filtered after the reaction is finished, and the reaction is dried in vacuum at 40 ℃ for 3h to obtain 22.56g of oxytetracycline chlorination product with the purity of 85.21 percent and the yield of 96.17 percent.
Example 15
Putting 480.07g of purified water into a 2L four-mouth bottle, adding 39.05g (AR, 99%) of sodium bicarbonate, then adding 29.98g of N-ethylacetamide (AR, 99%), stirring to fully mix, dropping 192.39g of sodium hypochlorite solution into the bottle when the temperature is reduced to 0 ℃, keeping the temperature for reaction for 10min after dropping, adding 270.06g of dichloromethane into the bottle after the reaction is finished, stirring for 10min, extracting and layering, adding 269.96g of dichloromethane into a water layer again for secondary extraction, mixing the chlorinated agent solutions obtained by the two extractions, mixing the chlorinated agent solutions, and obtaining the chlorinated agent with the mass of 549.32g after mixing, the detection content of 6.93% after mixing, the chlorinated agent with the mass of 38.07g, and calculating the product yield of 91.92%.
Adding 139.99g of methanol into a 500mL four-mouth bottle, adding 20.00g of oxytetracycline, cooling to-10 ℃, dissolving 1.33g of sodium acetate with 40.01g of methanol to serve as an auxiliary agent, taking 77.7g of dichloromethane solution of a chlorinating agent, simultaneously dripping the auxiliary agent and the dichloromethane solution of the chlorinating agent for 30min, reacting for 1h after dripping, filtering after the reaction is finished, and drying in vacuum at 40 ℃ for 3h to obtain 22.38g of oxytetracycline chlorination product with the purity of 87.18% and the yield of 97.90%.
To better demonstrate the preparation process of the invention, which allows to increase the yield of chlorinated product, 3 comparative examples are given, with reference to example 13.
Comparative example 1
The same operation as in example 13 was repeated, except that the reaction temperature in step (1) was 10 ℃. The mass after mixing was 542.32g, the detected content after mixing was 7.65%, the mass of the chlorinating agent was 41.49g, and the calculated product yield was 94.82%. The reaction temperature in step (2) was-15 ℃ and the rest of the operation was the same. 21.85g of terramycin chloride product is obtained, the purity is 85.76 percent, and the yield is 93.60 percent.
Comparative example 2
The same operation as in example 13 was repeated except that the reaction temperature in step (1) was set to 5 ℃. The mass of the mixture after mixing is 548.15g, the detection content is 7.68 percent after mixing, the mass of the chlorinating agent is 42.10g, and the calculated product yield is 96.22 percent. The reaction temperature in step (2) was-8 ℃ and the rest of the operation was the same. 22.64g of terramycin chloride product was obtained with a purity of 84.33% and a yield of 95.37%.
Comparative example 3
In contrast to example 13, in step (2) sodium acetate was added in a molar ratio to oxytetracycline of 0.5:1 in a ratio of 1. The same operation was followed to give 21.85g of oxytetracycline chloride product with a purity of 83.76% and a yield of 91.42%.
The present patent is not limited to the above-mentioned embodiments, and those skilled in the art can make various changes without creative efforts from the above-mentioned conception, and fall within the protection scope of the present patent.
Claims (6)
1. A preparation method of a doxycycline intermediate is characterized by comprising the following steps of:
(1) Preparation of chlorinated agent: dissolving an amide compound in water, adding sodium bicarbonate according to the molar ratio of 1.2-1.5 to the amide compound to 1, uniformly stirring, adding a sodium hypochlorite solution according to the molar ratio of 1-1.1 to the amide compound to 1 within 30-40min, controlling the reaction temperature to be 0-10 ℃, carrying out heat preservation reaction for 8-15min, adding dichloromethane, continuing stirring, standing for layering, and collecting a lower layer, namely a solution containing a chlorinating agent; wherein the amide compound is N-methylformamide, N-methylacetamide, N-ethylformamide or N-ethylacetamide;
(2) Preparation of doxycycline intermediate: taking oxytetracycline, adding methanol, stirring and mixing uniformly, cooling to-15-8 ℃, adding a sodium acetate solution according to the molar ratio of sodium acetate to oxytetracycline of 0.2-0.5.
2. The preparation method of the doxycycline intermediate as claimed in claim 1, wherein in step (1), the amide compound is N-ethylformamide, sodium bicarbonate is added according to a molar ratio of N-ethylformamide of 1.35.
3. The method for preparing a doxycycline intermediate as claimed in claim 2, wherein in step (1), the reaction temperature is controlled at 0 ℃ and the incubation reaction is carried out for 10min.
4. The method for preparing the doxycycline intermediate according to claim 1, wherein the chlorinating agent solution is added in the step (2) according to the molar ratio of the chlorinating agent to the oxytetracycline 1 being 1.1.
5. The method for preparing the doxycycline intermediate as claimed in claim 4, wherein in step (2), a sodium acetate solution is added according to the ratio of the molar ratio of sodium acetate to oxytetracycline (0.4).
6. The process for preparing a doxycycline intermediate as claimed in claim 1, wherein the temperature of the incubation in step (2) is-10 ℃.
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