CN114105792B - Preparation method of ciprofloxacin key intermediate - Google Patents
Preparation method of ciprofloxacin key intermediate Download PDFInfo
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
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Abstract
The invention provides a preparation method of a ciprofloxacin key intermediate, which solves the technical problems of unreasonable existing preparation method, high price and toxicity of raw materials, complex operation, high cost, low yield and unsuitability for industrial production, and the method takes 2, 4-dichloro-5-fluorobenzoyl methyl acetate, carbon monoxide and sodium methoxide as raw materials to carry out carbonylation reaction to generate (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol sodium, and then generates 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) prop-2-enoic acid methyl ester by ammoniation reaction with cyclopropylamine hydrochloride. The invention can be widely applied to the technical field of organic synthesis.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a ciprofloxacin key intermediate.
Background
In patent CN 104292159A, "a preparation method of norfloxacin, ciprofloxacin and enrofloxacin", 2, 4-5-fluorochlorobenzoyl chloride reacts with n, n-dimethylamino acrylate under the action of an acid-binding agent, and then the reaction product is exchanged with cyclopropylamine in an organic solvent to prepare the norfloxacin, ciprofloxacin and enrofloxacin. The reaction steps are simple, but the raw material cost is high, the reaction condition time is long, the organic solvent dosage is large, the post-treatment difficulty caused by using a plurality of inorganic base catalysts is high, and the pressure on equipment and three-waste treatment is large.
The (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) propyl-2-methyl enoate is a key intermediate for synthesizing ciprofloxacin, and at present, the industrial production at home and abroad mainly has two modes: the first one is prepared with 2, 4-dichloro-5-fluoro acetophenone as material, and through condensation with dimethyl (ethyl) carbonate, ethoxylation and amination with triethyl orthoformate. But the process has the disadvantages of harsh reaction conditions, long reaction time, expensive triethyl formate, low yield and high pollution. Secondly, on the existing route, the second step of the ethoxylation and methylenation is mainly improved, and the preparation solution of dimethyl sulfate and N, N-dimethylformamide is used for replacing expensive triethyl orthoformate, so that the cost is reduced, and the yield is higher. But dimethyl sulfate used in the reaction process belongs to a toxic tube product, so that the toxicity is high, the harm is high, N-dimethylformamide is heavy in taste in the use process, and the price is relatively low, so that the higher cost and the environmental protection pressure are not met.
Disclosure of Invention
The invention aims to solve the defects of the background technology and provides the preparation method of the ciprofloxacin key intermediate, which has the advantages of simple process steps, less early investment, simple post-treatment, good selectivity and high yield.
Therefore, the invention provides a preparation method of a ciprofloxacin key intermediate, which comprises the following specific steps:
(1) Carbonylation reaction: in a low-polarity solvent in a high-pressure reaction kettle, 2, 4-dichloro-5-fluorobenzoyl methyl acetate and sodium methoxide are taken as raw materials, carbon monoxide is charged, and carbonylation reaction is carried out to generate (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol sodium, and the specific reaction formula is as follows:
(2) Ammoniation reaction: adding the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol generated in the step (1) into a four-mouth bottle, adding cyclopropylamine hydrochloride, and carrying out an ammoniation reaction to generate 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) prop-2-enoic acid methyl ester, wherein the specific reaction formula is as follows:
preferably, the molar ratio of methyl 2, 4-dichloro-5-fluorobenzoylacetate to sodium methoxide in step (1) is 1.02 to 1.06.
Preferably, in the step (1), the carbonylation reaction temperature is 35-65 ℃, the reaction time is 2-4h, and the reaction pressure is 3.0-5.0MPa.
Preferably, in step (2), the molar ratio of methyl 2, 4-dichloro-5-fluorobenzoylacetate to cyclopropylamine hydrochloride is 1.05 to 1.12.
Preferably, in the step (2), the amination reaction temperature is 50 to 70 ℃.
Preferably, in the step (1), before the carbon monoxide is introduced, nitrogen is used for substitution three times, and then carbon monoxide is used for substitution three times.
Preferably, in step (2), after completion of the amination reaction, the mixture is stored at-10 ℃ for 24 hours.
Preferably, in the step (1), the low-polarity solvent is one or more of dimethyl carbonate, toluene and cyclohexane.
The beneficial effects of the invention are as follows:
(1) The invention provides a preparation method of a ciprofloxacin key intermediate, which provides a brand new synthesis route, and takes 2, 4-dichloro-5-fluorobenzoyl methyl acetate, carbon monoxide and sodium methoxide as raw materials to generate (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxo-prop-1-ene-1-sodium alcoholate through carbonylation reaction, and then the obtained product and cyclopropylamine hydrochloride are subjected to ammoniation reaction to generate 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) prop-2-enoic acid methyl ester. The method has the advantages of simple process steps, less investment in the early stage, high atom utilization rate, good selectivity, high yield and no three wastes, avoids high three-waste treatment cost compared with the traditional process, and is suitable for industrial production.
(2) Compared with the traditional process, the method avoids using expensive triethyl orthoformate, has low production cost, avoids using dimethyl sulfate with strong toxicity and N, N-dimethylformamide with heavier taste, has small environmental protection pressure and is environment-friendly, and the three wastes generated in the preparation process of the final 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) propyl-2-methyl enoate are obviously reduced. In addition, the sodium chloride generated by the invention can be recycled, so that the cost can be saved, the post-treatment is simple, the total yield of the 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) propyl-2-methyl enoate still reaches a higher level, the economic benefit is obviously improved, and the future green chemical development direction is met.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
Example 1
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle with nitrogen at 0.5MPa for three times, replacing nitrogen in the kettle with carbon monoxide for three times, charging carbon monoxide to 3.0MPa, heating in water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction is finished, the reaction product is cooled to room temperature, carbon monoxide is carefully discharged, the reaction product is cooled to 10 ℃, the reaction product is filtered, 20g of methanol is used for rinsing, and the reaction product is dried at 40 ℃ to obtain 23.01g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, wherein the liquid phase content is 99.11 percent, and the carbonylation reaction yield is 96.76 percent.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) to a 250ml four-mouth bottle, adding 50g of toluene, building a reflux device, heating to 60 ℃ to dissolve, dropwise adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and then preserving heat at 60 ℃ for 30min. And after heat preservation is finished, cooling to room temperature, placing in a refrigerator, preserving at-10 ℃ for 24h, performing suction filtration, rinsing a filter cake with 10g of 5 ℃ ice methanol, washing the obtained white solid with 20g of purified water for three times, and drying to obtain 22.85g of white solid, wherein the liquid phase content is 99.45%, and the molar yield is 94.21%.
The total yield of key intermediates for preparing ciprofloxacin is 91.15%.
Example 2
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.24g of sodium methoxide solid (1.04 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing the air in the kettle with nitrogen at 0.5MPa for three times, replacing the nitrogen in the kettle with carbon monoxide for three times, charging carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was carefully discharged, cooled to 10 ℃, filtered, rinsed with 20g of methanol, and dried at 40 ℃ to obtain 23.09g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, the liquid phase content was 99.11%, and the carbonylation yield was 97.10%.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and then preserving the temperature at 60 ℃ for 30min. And after heat preservation is finished, cooling to room temperature, placing in a refrigerator, preserving at-10 ℃ for 24h, performing suction filtration, rinsing a filter cake with 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid with 50g of purified water for three times, and drying to obtain 22.95g of white solid, wherein the liquid phase content is 99.22%, and the molar yield is 94.29%.
The total yield of key intermediates for preparing ciprofloxacin is 91.47%.
Example 3
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 25 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction is finished, the reaction product is cooled to room temperature, carbon monoxide is carefully discharged, the reaction product is cooled to 10 ℃, the reaction product is filtered, 20g of methanol is used for rinsing, and the reaction product is dried at 40 ℃ to obtain 20.37g of (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol sodium, wherein the liquid phase content is 99.21 percent, and the carbonylation reaction yield is 85.66 percent.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and keeping the temperature at 60 ℃ for 30min. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator, storing for 24h at the temperature of-10 ℃, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 20.30g of white solid, wherein the liquid phase content is 99.32%, and the molar yield is 94.55%.
The total yield of key intermediate for preparing ciprofloxacin is 80.99%.
Example 4
(1) Carbonylation reaction: a250 ml high-pressure reaction kettle is taken and added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the using amount of the solvent is 5 times of the adding amount of the 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the reaction kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 2.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure of 2.0MPa for reaction for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was carefully discharged, cooled to 10 ℃, filtered, rinsed with 20g of methanol, and dried at 40 ℃ to obtain 22.45g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, the liquid phase content was 99.27%, and the carbonylation yield was 94.41%.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and keeping the temperature at 60 ℃ for 30min. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator to be stored at the temperature of 10 ℃ below zero for 24 hours, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 22.31g of white solid, wherein the liquid phase content is 99.32 percent, and the molar yield is 94.25 percent.
The total yield of key intermediates for preparing ciprofloxacin is 80.98%.
Example 5
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 6 hours. After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was carefully discharged, cooled to 10 ℃, filtered, rinsed with 20g of methanol, and dried at 40 ℃ to obtain 22.69g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, the liquid phase content was 99.33%, and the carbonylation yield was 95.42%.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and keeping the temperature at 60 ℃ for 30min. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator, storing at the temperature of 10 ℃ below zero for 24 hours, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 22.53g of white solid, wherein the liquid phase content is 99.12 percent, and the molar yield is 94.19 percent.
The total yield of key intermediates for preparing ciprofloxacin is 89.88%.
Example 6
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester) and 100g of methanol (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was carefully discharged, cooled to 10 ℃, filtered, rinsed with 20g of methanol, and dried at 40 ℃ to obtain 13.84g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, the liquid phase content was 99.21%, and the carbonylation yield was 58.20%.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and then preserving the temperature at 60 ℃ for 30min. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator, storing at the temperature of 10 ℃ below zero for 24 hours, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 13.79g of a white solid, wherein the liquid phase content is 99.32%, and the molar yield is 94.52%.
The aggregate total yield of key intermediates in the preparation of ciprofloxacin is 55.01%.
Example 7
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction is finished, the reaction product is cooled to room temperature, carbon monoxide is carefully discharged, the reaction product is cooled to 10 ℃, the reaction product is filtered, 20g of methanol is used for rinsing, and the reaction product is dried at 40 ℃ to obtain 22.98g of (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol sodium, wherein the liquid phase content is 99.31 percent, and the carbonylation reaction yield is 96.64 percent.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 60 ℃, adding 7.63g of cyclopropylamine hydrochloride (1.08 equivalents of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and then preserving the temperature for 30min at 60 ℃. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator to be stored at the temperature of 10 ℃ below zero for 24 hours, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 23.11g of white solid, wherein the liquid phase content is 99.36 percent, and the molar yield is 95.38 percent.
The aggregate total yield of key intermediates for the preparation of ciprofloxacin was 92.18%.
Example 8
(1) Carbonylation reaction: a250 ml high pressure reaction kettle is taken to be added with 20g of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester, 4.16g of sodium methoxide solid (1.02 equivalent of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), 100g of cyclohexane (the dosage of the solvent is 5 times of the dosage of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester), and the kettle is combined. Replacing air in the kettle for 3 times by using nitrogen with the pressure of 0.5MPa, replacing nitrogen in the kettle for three times by using carbon monoxide, filling carbon monoxide to the pressure of 3.0MPa, heating in a water bath until the temperature in the kettle reaches 50 ℃, constantly paying attention to the pressure condition in the kettle and constantly maintaining the pressure at 3.0MPa for reaction for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was carefully discharged, cooled to 10 ℃, filtered, rinsed with 20g of methanol, and dried at 40 ℃ to obtain 22.97g of sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol, the liquid phase content was 99.31%, and the carbonylation reaction yield was 96.59%.
(2) Ammoniation reaction: transferring the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol prepared in the step (1) into a 250ml four-mouth bottle, building a reflux device, heating to 30 ℃, adding 7.42g of cyclopropylamine hydrochloride (1.05 equivalent of methyl 2, 4-dichloro-5-fluorobenzoylacetate), and then preserving the temperature for 30min at 30 ℃. And after the heat preservation is finished, cooling to room temperature, placing the mixture into a refrigerator to be stored at the temperature of 10 ℃ below zero for 24 hours, performing suction filtration, rinsing a filter cake by using 10g of 5 ℃ ice methanol, collecting a solid, washing the obtained white solid by using 50g of purified water for three times, and drying to obtain 20.30g of white solid, wherein the liquid phase content is 99.33 percent, and the molar yield is 83.82 percent.
The total yield of key intermediates for preparing ciprofloxacin is 80.96%.
TABLE 1 EXAMPLES 1-8 Experimental data parameters and results
In Table 1, sodium methoxide represents the molar ratio of sodium methoxide to the amount of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester added, and cyclopropylamine hydrochloride represents the molar ratio of cyclopropylamine hydrochloride to the amount of 2, 4-dichloro-5-fluorobenzoylacetic acid methyl ester added.
As can be seen from the data results in the above summary tables of experimental parameters and results of examples 1 to 8, in the step (1) of the carbonylation reaction, (1) the molar ratio of the amounts of sodium methoxide and methyl 2, 4-dichloro-5-fluorobenzoylacetate added, (2) the carbonylation reaction temperature, (3) the carbonylation reaction pressure, (4) the carbonylation reaction time, (5) the low-polarity solvent; in the ammonification reaction in the step (2), (6) the cyclopropylamine hydrochloride is the molar ratio of the cyclopropylamine hydrochloride to the addition amount of methyl 2, 4-dichloro-5-fluorobenzoylacetate, and (7) factors such as the ammonification reaction temperature and the like respectively have certain influence on the reaction yield and the total yield of each step, wherein the influence of the carbonylation reaction temperature on the yield of the condensation reaction in the step (1) is large; the ammoniation reaction temperature has the greatest influence on the yield of the ammoniation reaction in the step (2), and the complete degree of each step of the final carbonylation reaction and the ammoniation reaction has great influence on the total yield of the reaction.
(2) Examples 9-22 since the overall reaction sequence and reaction parameters are similar to those of example 1, except for individual parameter changes, the specific experimental steps are not detailed and the experimental data parameters and results for examples 1 and 9-22 are summarized below in table 2:
TABLE 2 summary of parameters and results of experimental data for example 1 and examples 9-22
In Table 2, sodium methoxide is the molar ratio of sodium methoxide to methyl 2, 4-dichloro-5-fluorobenzoylacetate, and cyclopropylamine hydrochloride is the molar ratio of cyclopropylamine hydrochloride to methyl 2, 4-dichloro-5-fluorobenzoylacetate.
From the data and results in the summary table of the experimental data and results of examples 1 and 9 to 22 above, it can be seen that (1) in the carbonylation reaction, (1) sodium methoxide and methyl 2, 4-dichloro-5-fluorobenzoylacetate are added in a molar ratio of 1.02 to 1.06, (2) the carbonylation reaction temperature is 35 to 65 ℃, (3) the carbonylation reaction pressure is 3.0 to 5.0MPa, (4) the carbonylation reaction time is 2 to 4 hours, and (5) the low-polarity solvent is one or more of dimethyl carbonate, toluene and cyclohexane; in the ammonification reaction in the step (2), (6) the molar ratio of cyclopropylamine hydrochloride to the addition amount of methyl 2, 4-dichloro-5-fluorobenzoylacetate is 1.05 to 1.12, and (7) when the ammonification reaction temperature is 50 to 70 ℃ and various parameters are changed, the preparation method of the ciprofloxacin key intermediate with high yield can be realized, wherein the combination of experimental parameters in the example 12 is excellent, and the total yield of the ciprofloxacin key intermediate reaches 93.10%.
The invention provides a preparation method of a ciprofloxacin key intermediate, and provides a brand new synthesis route.2, 4-dichloro-5-fluorobenzoyl methyl acetate, carbon monoxide and sodium methoxide are used as raw materials, carbonylation reaction is carried out to generate (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxo-prop-1-ene-1-sodium alcoholate, and the obtained product and cyclopropylamine hydrochloride are subjected to ammoniation reaction to generate 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) prop-2-enoic acid methyl ester. The method has the advantages of simple process steps, less investment in the early stage, high atom utilization rate, good selectivity, high yield and no three wastes, avoids high three-waste treatment cost compared with the traditional process, and is suitable for industrial production.
Compared with the traditional process, the method avoids using expensive triethyl orthoformate, has low production cost, avoids using dimethyl sulfate with strong toxicity and N, N-dimethylformamide with heavier taste, has small environmental protection pressure and is environment-friendly, and the three wastes generated in the preparation process of the final 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) propyl-2-methyl enoate are obviously reduced. In addition, the sodium chloride generated by the invention can be recycled, so that the cost can be saved, the post-treatment is simple, the total yield of the 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) propyl-2-methyl enoate still reaches a higher level, the economic benefit is obviously improved, and the future green chemical development direction is met.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (4)
1. A preparation method of a ciprofloxacin key intermediate is characterized by comprising the following steps:
(1) Carbonylation reaction: in a low-polarity solvent in a high-pressure reaction kettle, 2, 4-dichloro-5-fluorobenzoyl methyl acetate and sodium methoxide are taken as raw materials, carbon monoxide is charged, carbonylation reaction is carried out at the temperature of 35-65 ℃ to generate (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol sodium, the low-polarity solvent is one or more of dimethyl carbonate, toluene and cyclohexane, the molar ratio of the 2, 4-dichloro-5-fluorobenzoyl methyl acetate to the sodium methoxide is 1.02-1.06, the reaction pressure is 3.0-5.0MPa, and the specific reaction formula is as follows:
(2) Ammoniation reaction: adding the sodium (1Z) -3- (2, 4-dichloro-5-fluorophenyl) -2- (methoxycarbonyl) -3-oxoprop-1-en-1-ol generated in the step (1) into a four-mouth bottle, adding cyclopropylamine hydrochloride, carrying out an ammoniation reaction at the temperature of 50-70 ℃ to generate 3- (cyclopropylamino) -2- (2, 4-dichloro-5-fluorobenzoyl) prop-2-enoic acid methyl ester, and storing at the temperature of-10 ℃ for 24 hours after the ammoniation reaction is completed, wherein the specific reaction formula is as follows:
2. a method of preparing ciprofloxacin key intermediate as claimed in claim 1, wherein: in the step (1), the carbonylation reaction time is 2-4h.
3. A method of preparing ciprofloxacin key intermediate as claimed in claim 1, wherein: in step (2), the molar ratio of methyl 2, 4-dichloro-5-fluorobenzoylacetate to cyclopropylamine hydrochloride is 1.05-1.12.
4. A method of preparing ciprofloxacin key intermediate as claimed in claim 1, wherein: in the step (1), before the carbon monoxide is filled, nitrogen is used for replacing three times, and then carbon monoxide is used for replacing three times.
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