CN114716373B - Preparation method of gatifloxacin cyclized ester - Google Patents
Preparation method of gatifloxacin cyclized ester Download PDFInfo
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- CN114716373B CN114716373B CN202210394924.9A CN202210394924A CN114716373B CN 114716373 B CN114716373 B CN 114716373B CN 202210394924 A CN202210394924 A CN 202210394924A CN 114716373 B CN114716373 B CN 114716373B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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Abstract
The invention provides a preparation method of gatifloxacin cyclization ester. The preparation method is used for coupling reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride and N, N-dimethylamino ethyl acrylate under a negative pressure state, a cuprous halide catalyst is used, hydrogen chloride is led out in time, the reaction speed and the conversion rate are high, and three wastes are less; the cyclization reaction takes tri-n-propylamine as alkali, has high catalytic efficiency, small using amount and few impurities, and is easy to recover; in addition, the method can be carried out in a one-pot way, and has simple and convenient operation and lower cost. Therefore, the preparation method is a production process which is efficient, energy-saving, green and environment-friendly, simple to operate, simple in post-treatment, high in product yield and purity and good in atom economy, has extremely high economic and practical values, and is more suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of gatifloxacin cyclization ester.
Background
Gatifloxacin (AM-1155,1-cyclopropyl-6-fluoro-7- (3-methylpiperazin-1-yl) -8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid) is a fourth-generation quinolone antibacterial drug, is developed by Nippon apricot forest pharmaceutical company, makes up the defect that the third-generation quinolone drugs such as ciprofloxacin, ofloxacin and the like only act on gram-negative bacteria, has good antibacterial action on gram-positive bacteria, anaerobes, mycoplasma, chlamydia, mycobacteria and the like, hardly has potential photosensitive side reactions, is a safe and effective antibacterial drug, and has good development and application prospects.
The synthesis of gatifloxacin is firstly applied for a patent in Europe, the European patent number is EP0352123A2, 3,4,5,6-tetrafluorobenzene dicarboxylic acid is taken as a starting material, and a finished product is obtained by hydrolysis, decarboxylation, methylation, acylation, condensation, decarboxylation, alanine ester, cyclization, boronization and piperazine condensation reaction in sequence. Wherein, the cycloester of the gatifloxacin (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester) is a necessary key intermediate for synthesizing gatifloxacin.
EP0352123A2 reports that 3,4,5,6-tetrafluorophthalic acid is used as a starting material, and is subjected to hydrolysis, decarboxylation, methylation and acylation to generate 2,4,5-trifluoro-3-methoxybenzoyl chloride, 2,4,5-trifluoro-3-methoxybenzoyl chloride is condensed with diethyl ethylate-magnesium malonate to generate diethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) malonate, then the diethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) malonate is hydrolyzed under the action of p-toluenesulfonic acid to generate 3-oxo-3- (2,4,5-trifluoro-3-methoxyphenyl) propionate, then the diethyl 3-ethoxy-2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylate is reacted with triethyl orthoformate in an acetic anhydride solvent to generate ethyl 3- (cyclopropylamine) -2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylate, and finally the ethyl 3- (cyclopropylamine is aminated to generate cyclopropylamino) acrylate under the condition of DMF/thiofloxacin. Patent document CN1461748a reports that 2,4,5-tetrafluoro-3-methoxybenzoyl chloride is used as a starting material, and the quinolone main ring is obtained through substitution, hydrolysis decarboxylation, triethyl orthoformate condensation, enamine and cyclization. In the reaction, more byproducts are generated in decarboxylation and Grignard reactions, the product separation is difficult, the discharge amount of three wastes is large, and raw materials with high potential safety hazards such as triethyl orthoformate and the like are required to be used.
Patent documents CN110878082A and CN110357816a report that 2,4,5-trifluoro-3-methoxybenzoyl chloride is coupled with N, N-dimethylaminoethyl acrylate, then is replaced with cyclopropylamine, and finally undergoes cyclization under the action of strong base or potassium fluoride to form gatifloxacin cycloester; the acid-binding agent triethylamine is used in the coupling process, and strong base (sodium hydroxide, potassium hydroxide) or potassium fluoride is used in the cyclization process. The use of acid and alkali can increase the recovery process, the use of strong alkali in the cyclization process can damage materials, the yield is low, impurities are more, the use of potassium fluoride can generate other byproducts, the byproducts cannot be recycled, and the cost is high. In addition, in the prior art, organic bases such as DBU, triethylamine and the like are also used as catalysts in the cyclization process of the main ring of the quinolone, but the problems of large base consumption, low product yield, difficult recycling and the like exist.
Therefore, the search for more economical and efficient methods for preparing cyclized esters of floxacin is urgently needed.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of gatifloxacin cyclization ester, which is a high-efficiency green reaction process and has the outstanding advantages of high reaction speed, few synthesis steps, high product yield and purity, no pollutant discharge and the like.
Therefore, the invention provides a preparation method of gatifloxacin cyclization ester, which comprises the following steps:
1) Coupling reaction
2,4,5-trifluoro-3-methoxybenzoyl chloride, N-dimethylamino ethyl acrylate, a catalyst and an organic solvent are put into a reactor, the vacuum degree is controlled to be 0.05-0.09Mpa, the temperature is controlled to be 35-50 ℃, the reaction is carried out under reduced pressure and heat preservation to generate 3-dimethylamino-2- (2,4,5-trifluoro-3-methoxybenzoyl) ethyl acrylate, an absorption device is arranged in the process of carrying out coupling reaction under reduced pressure, and hydrogen chloride is absorbed by water to obtain a byproduct hydrochloric acid; after the reaction is completed, breaking vacuum by using inert gas, cooling to 0-15 ℃, dropwise adding cyclopropylamine, and after the dropwise adding is completed, carrying out heat preservation reaction at 25-40 ℃ to generate 3-cyclopropylamino-2- (2,4,5-trifluoro-3-methoxybenzoyl) ethyl acrylate; decompressing and recovering the dimethylamine gas, and directly using the amination liquid for the next cyclization reaction after the catalyst is recovered by a filter;
2) Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding tri-n-propylamine, sealing the kettle, heating to 120-150 ℃ under the protection of inert gas, keeping the temperature to 0.2-0.5Mpa, reacting, cooling to 60-80 ℃ after complete reaction, transferring into a crystallization kettle, cooling to 0-10 ℃ for crystallization, filtering, washing with an organic solvent, and drying to obtain a finished gatifloxacin cyclization ester.
In one embodiment of the present invention, the preparation method further comprises a process of recycling raw materials, specifically comprising: combining the mother liquor and the washing liquid in the step 2, adding the recovered hydrochloric acid aqueous solution in the step 1, keeping the pH =1-2, extracting and layering, wherein the upper layer is an organic phase, and the recovered organic solvent is mechanically applied to the feeding in the step 1; and transferring the lower layer of the aqueous phase into a tri-n-propylamine alkali regulation kettle, regulating the pH value to be =9-10 by using liquid alkali, extracting and layering, wherein the upper layer of the aqueous phase is the tri-n-propylamine, and mechanically applying the aqueous phase after dehydration, and decompressing and recovering the residual aqueous phase to obtain the byproduct sodium fluoride.
In the present invention, in the coupling reaction of step 1, the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to N, N-dimethylaminoethyl acrylate is 1.0-1.1, preferably 1.0-1.05, more preferably 1.0-1.01.
The catalyst is selected from at least one of cuprous chloride, cuprous bromide and cuprous iodide, and is preferably cuprous iodide. 2,4,5-trifluoro-3-methoxybenzoyl chloride to catalyst in a molar ratio of 1.005 to 0.03, preferably 1.0.01 to 0.02, more preferably 1.0.
The organic solvent is selected from high-boiling water-immiscible organic solvents, preferably at least one of toluene and xylene, and more preferably toluene.
The vacuum degree of the coupling reaction is preferably 0.06-0.08MPa, and the reaction temperature is preferably 35-40 ℃.
Preferably, the reaction is carried out under reduced pressure for 1 to 10 hours, more preferably 2 to 6 hours.
Preferably, the temperature is reduced to 5-10 ℃, and then the cyclopropylamine is added dropwise.
Preferably, cyclopropylamine is used in an amount such that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to cyclopropylamine is from 1.0 to 1.1, preferably from 1.0 to 1.05, more preferably from 1.0 to 1.01.
Preferably, the dripping time of the cyclopropylamine is 0.5 to 2 hours. The reaction temperature is preferably 25-30 ℃ after the addition is completed. The reaction time is kept for 1 to 4 hours, preferably 2 to 3 hours.
Preferably, when the dimethylamine gas is recovered under reduced pressure, the vacuum degree is controlled to be 0.05-0.09Mpa, and the temperature is controlled to be 20-35 ℃; more preferably, the vacuum degree is controlled to be 0.06-0.08MPa, and the temperature is controlled to be 25-30 ℃.
In the invention, the byproduct hydrochloric acid in the step 1 can be sold as a product and can also be used for recovering and treating the solvent toluene; preferably, it is used for solvent toluene recovery treatment. The byproduct dimethylamine can be sold. The catalyst recovered by the filter can be applied to the next coupling reaction.
In the present invention, tri-n-propylamine is used in the cyclization reaction of step 2 in such an amount that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to tri-n-propylamine is 1.0 to 1.0, preferably 1.0.
Preferably, the temperature is raised to 130-140 ℃ and the pressure is 0.3-0.4MPa. Preferably, the reaction is carried out with incubation for 2 to 10 hours, preferably 3 to 6 hours.
Preferably, the temperature in the crystallization kettle is reduced to 0-5 ℃ for crystallization.
In the present invention, the inert gas is at least one selected from nitrogen and argon.
In the present invention, the liquid alkali is an aqueous solution of sodium hydroxide, and the concentration thereof is preferably 30 to 32%.
In the invention, the by-product sodium fluoride can be sold.
Has the advantages that:
the preparation method of the invention has the following characteristics:
1. the coupling reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride and N, N-dimethylamino ethyl acrylate is carried out for the first time under the negative pressure state, the cuprous halide catalyst is used, and the hydrogen chloride is led out in time, so that the reaction speed and the conversion rate are improved; the hydrogen chloride is directly used as a byproduct for treatment, a large amount of acid-binding agents are not needed, the recovery difficulty is reduced, and the cost is reduced.
2. The cyclization reaction takes tri-n-propylamine as alkali, and compared with strong alkali, triethylamine, DBU and the like, the method has the advantages of high catalytic efficiency, small using amount and few impurities, and the tri-n-propylamine is immiscible with water, is easy to recover and reuse by treating mother liquor, and reduces the cost.
3. The method can be carried out in a one-pot way, the separation of the intermediate is not needed, the operation is simplified, the cost is reduced, and meanwhile, the using amount of the solvent is less.
4. No pollutant is discharged into the environment in the whole production process, a closed-loop state is achieved, the purity of the byproduct is high, and all materials are easy to recycle or sell. The materials are fully utilized, and the atom economy is high.
5. The method has high conversion rate, the overall yield can reach more than 93.5 percent, and the product purity can reach more than 99.8 percent.
In a word, the preparation method of gatifloxacin cyclization ester is a production process which is efficient, energy-saving, green and environment-friendly, simple in operation, simple in post-treatment, high in product yield and purity and good in atom economy, has extremely high economic and practical values, and is more suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of the product of example 1.
Detailed Description
Hereinafter, preferred examples of the invention will be described in detail. The examples are given for the purpose of better presenting the summary and are not intended to be limiting. Insubstantial modifications and adaptations of the embodiments in accordance with the present disclosure remain within the scope of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications.
Example 1:
1. coupling reaction
Adding 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate into a reaction kettle: 29g (0.2024mol, 1.01 times of the weight of the hydrochloric acid), 150ml of toluene, 0.5g of cuprous iodide, the vacuum degree is controlled to be 0.06-0.07Mpa, the temperature is controlled to be 35-40 ℃, the temperature is reduced under reduced pressure and is kept for 3 hours, the reaction raw material point is controlled to be less than or equal to 0.5 percent, the reaction is complete, an absorption device is arranged in the reduced pressure process, the hydrogen chloride is absorbed by water, and the byproduct hydrochloric acid is used for the next step of recovering and treating the solvent toluene.
After the reaction is completed, breaking vacuum by using nitrogen, reducing the temperature to 5-10 ℃, dropwise adding 11.44g (0.2004mol, 1 time) of cyclopropylamine, and consuming 1h. After the dripping is finished, the temperature is kept for 2 hours at 25-30 ℃, and the reaction raw material point is controlled to be less than or equal to 0.3 percent. Controlling the vacuum degree at 0.06-0.07Mpa and the temperature at 25-30 ℃, decompressing and recovering the dimethylamine gas, washing the dimethylamine gas to be sold as a byproduct, and recovering the catalyst from the amination solution through a filter to be directly used for the next cyclization reaction.
2. Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding 27.28g (0.1904 mol,0.95 times) of tri-n-propylamine, sealing the kettle, replacing three times by using nitrogen, heating to 140 ℃, keeping the pressure at 0.3-0.35Mpa, reacting for 4 hours at a constant temperature, cooling to 70-75 ℃, transferring into a crystallization kettle, cooling to 0-5 ℃, filtering, washing with toluene, and drying to obtain a finished product 61.54g. The molar yield was 95.0% (based on 2,4,5-trifluoro-3-methoxybenzoyl chloride) and the product purity was 99.8% (HPLC spectrum see figure 1).
And (2) combining the mother liquor and the washing liquid, adding the recovered hydrochloric acid aqueous solution obtained in the step (1), keeping the pH value to be =1-2, extracting and layering, wherein the upper layer is a toluene layer, recycling and applying to the coupling reaction obtained in the step (1) for feeding, transferring the water phase to a tri-n-propylamine alkali regulation kettle, regulating the pH value to be =9-10 by using liquid alkali, extracting and layering, wherein the upper layer is tri-n-propylamine, dehydrating and applying to the kettle, and decompressing and recovering the residual water phase to obtain the byproduct sodium fluoride.
Example 2:
1. coupling reaction
Adding 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate into a reaction kettle: 29g (0.2024mol, 1.01 times), 150ml of methylbenzene, 0.3g of cuprous iodide, controlling the vacuum degree to be 0.06-0.07Mpa, controlling the temperature to be 35-40 ℃, reducing the pressure and preserving the heat for 3 hours, controlling the reaction raw material point to be less than or equal to 0.5 percent, completely reacting, absorbing hydrogen chloride by water in the pressure reduction process by an absorption device, and obtaining byproduct hydrochloric acid for the next step of recovering and treating the methylbenzene as the solvent.
After the reaction is completed, breaking vacuum by using nitrogen, reducing the temperature to 5-10 ℃, dropwise adding 11.44g (0.2004mol, 1 time) of cyclopropylamine, and consuming 1h. After the dripping is finished, the temperature is kept for 2 hours at 25-30 ℃, and the reaction raw material point is controlled to be less than or equal to 0.3 percent. Controlling the vacuum degree at 0.06-0.07Mpa and the temperature at 25-30 ℃, decompressing and recovering the dimethylamine gas, washing the dimethylamine gas to be sold as a byproduct, and recovering the catalyst from the amination solution through a filter to be directly used for the next cyclization reaction.
2. Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding 27.28g (0.1904 mol,0.95 times) of tri-n-propylamine, sealing the kettle, replacing three times by using nitrogen, heating to 140 ℃, keeping the pressure at 0.3-0.35Mpa, reacting for 4 hours at a constant temperature, cooling to 70-75 ℃, transferring into a crystallization kettle, cooling to 0-5 ℃, filtering, washing with toluene, and drying to obtain a finished product 60.77g. The molar yield is 93.8%, and the product purity is 99.8%.
The mother liquor was worked up as in example 1.
Example 3:
1. coupling reaction
2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate are put into a reaction kettle: 29g (0.2024mol, 1.01 times of the weight of the hydrochloric acid), 150ml of toluene, 0.75g of cuprous iodide, the vacuum degree of 0.06-0.07Mpa, the temperature of 35-40 ℃, the reduced pressure and the heat preservation for 3 hours, the reaction raw material point is controlled to be less than or equal to 0.5 percent, the reaction is complete, an absorption device is arranged in the reduced pressure process, the hydrogen chloride is absorbed by water, and the byproduct hydrochloric acid is used for the next step of recovering and treating the solvent toluene.
After the reaction is completed, breaking vacuum by using nitrogen, reducing the temperature to 5-10 ℃, dropwise adding 11.44 (0.2004mol, 1 time) of cyclopropylamine, and consuming 1h. After the dripping is finished, the temperature is kept for 2 hours at 25-30 ℃, and the reaction raw material point is controlled to be less than or equal to 0.3 percent. Controlling the vacuum degree at 0.06-0.07Mpa and the temperature at 25-30 ℃, decompressing and recovering the dimethylamine gas, washing the dimethylamine gas to be sold as a byproduct, and recovering the catalyst from the amination solution through a filter to be directly used for the next cyclization reaction.
2. Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding 27.28g (0.1904 mol,0.95 times) of tri-n-propylamine, sealing the kettle, replacing three times by using nitrogen, heating to 140 ℃, keeping the pressure at 0.3-0.35Mpa, reacting for 4 hours at a constant temperature, cooling to 70-75 ℃, transferring into a crystallization kettle, cooling to 0-5 ℃, filtering, washing with toluene, and drying to obtain a finished product 61.80g. The molar yield is 95.4%, and the product purity is 99.8%.
The mother liquor was worked up as in example 1.
Example 4:
1. coupling reaction
Adding 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate into a reaction kettle: 29g (0.2024mol, 1.01 times), 150ml of methylbenzene, 0.3g of cuprous chloride, controlling the vacuum degree to be 0.06-0.07Mpa, controlling the temperature to be 35-40 ℃, reducing the pressure and preserving the heat for 3 hours, controlling the reaction raw material point to be less than or equal to 0.5 percent, completely reacting, absorbing hydrogen chloride by water in the pressure reduction process by an absorption device, and obtaining byproduct hydrochloric acid for the next step of recovering and treating the methylbenzene as the solvent.
After the reaction is completed, breaking vacuum by using nitrogen, reducing the temperature to 5-10 ℃, dropwise adding 11.44g (0.2004mol, 1 time) of cyclopropylamine, and consuming 1h. After the dripping is finished, the temperature is kept for 2 hours at 25-30 ℃, and the reaction raw material point is controlled to be less than or equal to 0.3 percent. Controlling the vacuum degree at 0.06-0.07Mpa and the temperature at 25-30 ℃, decompressing and recovering the dimethylamine gas, washing the dimethylamine gas to be sold as a byproduct, and directly using the amination liquid for the next cyclization reaction.
2. Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding 27.28g (0.1904 mol,0.95 times) of tri-n-propylamine, sealing the kettle, replacing three times by using nitrogen, heating to 140 ℃, keeping the pressure at 0.3-0.35Mpa, reacting for 4 hours at a constant temperature, cooling to 70-75 ℃, transferring into a crystallization kettle, cooling to 0-5 ℃, filtering, washing with toluene, and drying to obtain a finished product 60.97g. The molar yield is 94.1%, and the product purity is 99.8%.
The mother liquor was worked up as in example 1.
Comparative example 1:
2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate are put into a reaction kettle: 29g (0.2024mol, 1.01 times of) of toluene, 150ml of toluene, controlling the vacuum degree to be 0.06-0.07Mpa, controlling the temperature to be 35-40 ℃, reducing pressure and preserving heat for 10 hours, arranging an absorption device in the pressure reduction process, and absorbing hydrogen chloride by water; the reaction solution was analyzed, and the conversion of 2,4,5-trifluoro-3-methoxybenzoyl chloride was only 54%.
Comparative example 2:
adding 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 time) and N, N-dimethylamino ethyl acrylate into a reaction kettle: 29g (0.2024mol, 1.01 times of the amount), 150ml of toluene and 0.5g of cuprous iodide, controlling the temperature to be 35-40 ℃, and carrying out heat preservation reaction for 8 hours; the reaction solution was analyzed, and the conversion of 2,4,5-trifluoro-3-methoxybenzoyl chloride was only 19%.
Comparative example 3:
1. coupling reaction
Adding N, N-dimethylamino ethyl acrylate into a reaction kettle: 29g (0.2024mol, 1.01 times of the total amount), 150ml of toluene, 20.68g of triethylamine (0.2044mol, 1.02 times of the total amount), controlling the temperature to 35-40 ℃, dropwise adding 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.2004mol, 1 time of the total amount), dropwise adding for about 1-2h, heating to 55-65 ℃ after dropwise adding, keeping the temperature for 3h, controlling the reaction raw material point to be less than or equal to 0.5 percent, and directly using for next ammoniation reaction.
After the reaction is completed, the temperature is reduced to 20 to 30 ℃, 11.44g (0.2004mol, 1 time) of cyclopropylamine is directly added, the temperature is kept for 2 hours at 25 to 30 ℃, and the point of the reaction raw material is controlled to be less than or equal to 0.3 percent. And (3) after the reaction is finished, transferring the amination solution into dilute hydrochloric acid aqueous solution (70 ml of 31% hydrochloric acid and 200ml of water), uniformly stirring, standing for layering, decompressing an upper toluene layer, recovering toluene, recovering to dryness, adding 50ml of DMF (dimethyl formamide) to dissolve the amination solution, and dissolving the amination solution for the next step of cyclization reaction.
2. Cyclization reaction
Adding 400ml of DMF into a cyclization reaction kettle, adding 31.5g of potassium fluoride under stirring, heating to 145-155 ℃, dropwise adding the amination solution obtained in the previous step, dropwise adding for 4 hours, carrying out heat preservation reaction for 0.5 hour, completely reacting, filtering while the solution is hot, transferring the filtrate into a recovery kettle, carrying out reduced pressure recovery, controlling the vacuum degree to be more than 0.08MPa, stopping recovery after recovering 250ml, cooling to 0-5 ℃, filtering, washing with water, and drying to obtain 53.32g of a finished product. The molar yield is 82.3%, and the product purity is 98.2%.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (14)
1. A preparation method of gatifloxacin cyclization ester comprises the following steps:
1) Coupling reaction
Putting 2,4,5-trifluoro-3-methoxybenzoyl chloride, N-dimethylamino ethyl acrylate, a catalyst and an organic solvent into a reactor, controlling the vacuum degree to be 0.05-0.09Mpa and the temperature to be 35-50 ℃, carrying out reduced pressure and heat preservation reaction to generate 3-dimethylamino-2- (2,4,5-trifluoro-3-methoxybenzoyl) ethyl acrylate, installing an absorption device in the process of carrying out coupling reaction under reduced pressure, and absorbing hydrogen chloride by water to obtain a byproduct hydrochloric acid; after the reaction is completed, breaking vacuum by using inert gas, cooling to 0-15 ℃, dropwise adding cyclopropylamine, and after the dropwise adding is completed, carrying out heat preservation reaction at 25-40 ℃ to generate 3-cyclopropylamino-2- (2,4,5-trifluoro-3-methoxybenzoyl) ethyl acrylate; decompressing and recovering the dimethylamine gas, and directly using the amination liquid for the next cyclization reaction after the catalyst is recovered by a filter; wherein the catalyst is selected from at least one of cuprous chloride and cuprous iodide; the organic solvent is at least one of toluene and xylene;
2) Cyclization reaction
Transferring the amination solution into a cyclization reaction kettle, adding tri-n-propylamine, sealing the kettle, heating to 120-150 ℃ under the protection of inert gas, keeping the temperature to 0.2-0.5Mpa, reacting, cooling to 60-80 ℃ after complete reaction, transferring into a crystallization kettle, cooling to 0-10 ℃ for crystallization, filtering, washing with an organic solvent, and drying to obtain a finished gatifloxacin cyclization ester.
2. The method of manufacturing according to claim 1, further comprising: combining the mother liquor and the washing liquid in the step 2, adding the recovered hydrochloric acid aqueous solution in the step 1, keeping the pH =1-2, extracting and layering, wherein the upper layer is an organic phase, and the recovered organic solvent is mechanically applied to the feeding in the step 1; and transferring the lower layer to a tri-n-propylamine alkali regulation kettle, regulating the pH to be 9-10 by using liquid alkali, extracting and layering, wherein the upper layer is the tri-n-propylamine, and the upper layer is reused after dehydration, and the residual water phase is recovered under reduced pressure to obtain the byproduct sodium fluoride.
3. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to ethyl N, N-dimethylaminoacrylate is 1.0 to 1.1.
4. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to ethyl N, N-dimethylaminoacrylate is 1.0 to 1.05.
5. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to ethyl N, N-dimethylaminoacrylate is 1.0 to 1.01.
6. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to catalyst is 1.005-0.03.
7. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to catalyst is 1.0 to 0.02.
8. The process of claim 1, wherein the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to catalyst is 1.0 to 0.015.
9. The process of claim 1, wherein cyclopropylamine is used in an amount such that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to cyclopropylamine is from 1.0 to 1.1.
10. The process of claim 1, wherein cyclopropylamine is used in an amount such that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to cyclopropylamine is from 1.0 to 1.05.
11. The process of claim 1, wherein cyclopropylamine is used in an amount such that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to cyclopropylamine is from 1.0 to 1.01.
12. The process of claim 1 wherein tri-n-propylamine is used in an amount such that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to tri-n-propylamine is from 1.0 to 1.0.
13. The process of claim 1, wherein tri-n-propylamine is used in such an amount that the molar ratio of 2,4,5-trifluoro-3-methoxybenzoyl chloride to tri-n-propylamine is from 1.0 to 0.95 to 0.98.
14. The method according to claim 1, wherein the temperature is raised to 130 to 140 ℃ and the pressure is 0.3 to 0.4MPa in the cyclization reaction of step 2.
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