CN109721617B - Preparation method of tazobactam - Google Patents
Preparation method of tazobactam Download PDFInfo
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- CN109721617B CN109721617B CN201910089679.9A CN201910089679A CN109721617B CN 109721617 B CN109721617 B CN 109721617B CN 201910089679 A CN201910089679 A CN 201910089679A CN 109721617 B CN109721617 B CN 109721617B
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Abstract
The invention discloses a preparation method of tazobactam. The method uses 3, 5-dinitroThe method comprises the steps of carrying out esterification reaction on benzyl chloride which is a carboxyl protection reagent and 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide, then carrying out reduction, thermal cracking, chloromethylation, azidation, double oxidation and cycloaddition to obtain tazobactam 3, 5-dinitrobenzyl ester, then using palladium carbon as a catalyst, removing the protection of the tazobactam 3, 5-dinitrobenzyl ester by using hydrogen to obtain tazobactam, and reacting a byproduct 3, 5-dinitrotoluene with a chlorination reagent N-chlorosuccinimide to prepare 3, 5-dinitrobenzyl chloride to realize the recycling of the protection reagent.
Description
Technical Field
The invention relates to a preparation method of tazobactam, belonging to the technical field of medicines.
Background
Tazobactam is a novel penicillanic sulfone b-lactamase inhibitor developed by the pharmaceutical company of Roc, is one of β -lactamase inhibitors with the best clinical application effect at present, and has the characteristics of high stability, low activity, low toxicity, strong enzyme inhibition activity and the like, in 1992, tazobactam and piperacillin (1:8), which are compound medicines of tazobactam, are firstly marketed in France and are used for treating various bacterial infections.
The current synthetic route for tazobactam is as follows: the tazobactam is prepared by taking 6-APA as a raw material and sequentially carrying out the steps of bromination, oxidation, esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition, deprotection and the like, and the synthetic route is shown as follows.
In the third step of the esterification reaction in the above route, diazomethane formed by the reaction of peracetic acid and benzophenone hydrazone is generally used as a protection reagent to react with carboxyl to generate carboxylic acid diphenyl methyl ester, and m-cresol is generally adopted for deprotection in the deprotection step. The above process has the following defects:
1. the poor stability of the synthesis of the diphenyldiazomethane is easy to cause the decomposition and explosion of the peroxyacetic acid, so that the greater safety risk exists;
2. peroxide is needed to be destroyed in the post-treatment after the reaction, so that a large amount of salt-containing wastewater is generated, and the environmental protection pressure is higher;
3. in the deprotection step, m-cresol is used for deprotection to form a 2-benzhydryl m-cresol byproduct, which is difficult to recycle and only can be treated as hazardous waste, so that resource waste is caused.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of tazobactam. The method uses 3, 5-dinitrobenzyl chloride which has stable chemical property, high reaction activity and lower price as a carboxyl protection reagent, and then adopts palladium-carbon hydrogenation deprotection to obtain the tazobactam external byproduct 3, 5-dinitrotoluene which can react with N-chlorosuccinimide to generate 3, 5-dinitrobenzyl chloride, and the preparation method is cleaner and more environment-friendly.
The technical scheme of the invention is that the preparation method of tazobactam takes 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide as raw material, and is characterized in that the method comprises the steps of esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition and deprotection,
the esterification reaction is to react 3, 5-dinitrobenzyl chloride serving as a carboxyl protection reagent with 6 α -bromopenam-3 α -carboxylic acid-1 β -oxide (bromo-sulphoxide acid for short) to obtain 3, 5-dinitrobenzyl ester (compound 1), and the esterification reaction is further subjected to reduction, thermal cracking, chloromethylation, azidation, double oxidation and cycloaddition to obtain tazobactam 3, 5-dinitrobenzyl ester (compound 7);
the deprotection reaction is as follows: palladium carbon is used as a catalyst, and the protection of the tazobactam 3, 5-dinitrobenzyl ester is removed by hydrogen to obtain tazobactam (compound 8); the byproduct 3, 5-dinitrotoluene reacts with chlorinated reagent N-chlorosuccinimide to prepare 3, 5-dinitrobenzyl chloride, so that the cyclic utilization of the protective reagent is realized.
The reaction equation is as follows:
the reaction equation for preparing 3, 5-dinitrobenzyl chloride by reacting the byproduct 3, 5-dinitrotoluene with the chlorinating agent N-chlorosuccinimide is shown as follows:
further, the solvent used in the esterification reaction is an aprotic polar solvent such as DMF, acetone, acetonitrile, etc., preferably acetone.
Further, the esterification reaction temperature is 20-50 ℃, preferably 30-40 ℃.
Further, the acid-binding agent used in the esterification reaction is an inorganic weak base, such as sodium bicarbonate, potassium bicarbonate, and the like, preferably sodium bicarbonate.
Further, the solvent used for the deprotection reaction is dichloromethane or ethyl acetate, preferably dichloromethane.
Further, the deprotection reaction conditions are as follows: the pressure is normal pressure, the reaction temperature is 15-35 ℃, and the optimal temperature is 20-30 ℃;
further, the solvent used for the reaction of the by-product 3, 5-dinitrotoluene with N-chlorosuccinimide is DMF, acetone, acetonitrile, etc., preferably acetone.
Further, the reaction temperature of the byproduct 3, 5-dinitrotoluene and N-chlorosuccinimide is 20-40 ℃, preferably 25-35 ℃.
In the esterification reaction, the molar ratio of 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide to 3, 5-dinitro benzyl chloride to sodium bicarbonate is 1: 1.0-1.2.
Further, the mass ratio of the palladium-carbon catalyst for deprotection reaction to the tazobactam 3, 5-dinitrobenzyl ester is 1: 100 to 1000.
Further, the molar ratio of the 3, 5-dinitrotoluene to the N-chlorosuccinimide is 1: 0.9 to 1.1.
Preferably, the esterification reaction step specifically comprises the steps of adding 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide and 3, 5-dinitrobenzyl chloride into an acetone solvent, adding sodium bicarbonate, controlling the temperature to be 30-40 ℃ and reacting for 4-6 hours, adding water after the reaction is finished, stirring and filtering, washing with water, and drying to obtain the 3, 5-dinitrobenzyl ester.
Preferably, the deprotection reaction comprises the following specific steps: adding tazobactam 3, 5-dinitrobenzyl ester into dichloromethane serving as a solvent, adding palladium carbon, controlling the temperature to be 20-30 ℃, and introducing hydrogen to react for 3-4 hours; after the reaction is finished, adding sodium bicarbonate solution (0.05g/ml), stirring, layering, adding hydrochloric acid to acidify after a water layer is decolored (a dichloromethane layer is used for recovering 3, 5-dinitrotoluene) to separate out a product, performing suction filtration, washing with water, and drying to obtain white solid tazobactam acid.
Preferably, the preparation of the 3, 5-dinitrobenzyl chloride by the byproduct 3, 5-dinitrotoluene comprises the following steps: and (3) distilling the dichloromethane layer subjected to the deprotection reaction under reduced pressure to obtain a p-3, 5-dinitrotoluene oily substance, adding acetone, adding N-chlorosuccinimide, reacting at 25-35 ℃ for 5-8 hours, adding N-hexane after the reaction is finished, stirring for 1-2 hours, performing suction filtration, and drying to obtain the 3, 5-dinitrobenzyl chloride.
Compared with the prior art, the invention has the following advantages:
1. 3, 5-dinitrobenzyl chloride with stable chemical property, high reaction activity and lower price is used as a carboxyl protection reagent, so that the use of peroxyacetic acid which is poor in stability and easy to cause decomposability explosion is avoided, and the intrinsic safety of the process is realized;
2. the amount of waste water generated in the reaction is greatly reduced, and the environmental protection pressure can be greatly reduced;
3. the by-product 3, 5-dinitrotoluene reacts with chlorinated reagent chlorosuccinimide to prepare 3, 5-dinitrobenzyl chloride, so that the cyclic utilization of the protective reagent is realized.
Detailed Description
The present invention is illustrated by the following examples, wherein the experimental procedures of reduction, thermal cracking, chloromethylation, azidation, dioxygenation and cycloaddition are the same as the prior art, and the yield is the same as the prior art.
Example 1:
1) esterification reaction
29.6g (0.1mol) of bromosulfoxide is taken, transferred into a 500mL three-necked flask, added with 100g of acetone, added with 23.8g (0.11mol) of 3, 5-dinitrobenzyl chloride and 9.2g of sodium bicarbonate, and reacted for 4-6 hours at the temperature of 30-40 ℃ (the degree of reaction is monitored by TLC, a developing agent V ethyl acetate: V n-hexane is 1: 2). After the reaction is finished, 200g of water is added, stirred for 1-2 hours, filtered, washed and dried to obtain 45.2g of the solid of the compound 1, and the yield is 95.0%.
2) Reduction of
Dissolving 47.6g (0.1mol) of the solid of the compound 1 obtained in the previous step in 200mL of tetrahydrofuran, adding 100mL of water and 20.0g of ammonium acetate, controlling the temperature to be 0-10 ℃, adding 13.0g of zinc powder in batches, reacting for 2-3 hours under a heat preservation condition, filtering, separating an organic layer, distilling under reduced pressure until the organic layer is dry, adding 100mL of toluene for crystallization, filtering, leaching with a small amount of toluene, and drying to obtain 36.1g of the compound.
3) Thermal cracking, chloromethylation, azidation
Adding 200mL of toluene into 22.9g of the solid of the compound 2 obtained in the previous step, adding 15.0g of 2-mercaptobenzothiazole, heating and refluxing for 2.5 hours, carrying out thermal cracking reaction, cooling after the reflux is finished, distilling under reduced pressure until the mixture is nearly dry, adding 400mL of dichloromethane for dissolving, adding 100mL of 30% hydrochloric acid, cooling to-15-10 ℃, dropwise adding a sodium nitrite solution (6g of sodium nitrite is dissolved in 50g of water), carrying out thermal insulation reaction for 3-4 hours after the dropwise adding is finished, carrying out suction filtration, separating an organic layer, and washing the organic layer with 300mL of saturated sodium bicarbonate solution and 300mL of water. Distilling under reduced pressure to dryness, adding 200mL of mixed solution of sodium azide and sodium azide (20.0g of mixed solution of sodium azide and 100mL of mixed solution of sodium azide and sodium azide are dissolved in 100mL of mixed solution of sodium azide and sodium azide), controlling the temperature to be 30-40 ℃, preserving the temperature for 8 hours, adding 300mL of ethyl acetate and 200mL of water to extract after the heat preservation is finished, separating an organic layer, washing with 300mL of water, and distilling under reduced pressure to dryness to obtain an oily substance.
4) Double oxidation, cycloaddition
Dissolving the oily matter in 200mL of glacial acetic acid, controlling the temperature to be 20-30 ℃, adding 21.0g of potassium permanganate in batches for reaction, preserving the temperature for 5h after the addition, dropwise adding 10g of hydrogen peroxide to decompose unreacted potassium permanganate, adding 300mL of ethyl acetate and 300mL of water for extraction, adding 300mL of saturated sodium bicarbonate solution to wash an organic layer, layering, adding 300mL of purified water to wash and layering; reduced pressure distillation is carried out till the product is dry, 200mL of acetone is added for dissolution, the product is transferred into a high-pressure kettle, acetylene is introduced, the temperature is controlled to be 80-90 ℃, the pressure is 0.15-0.2MPa, the reaction is carried out for 10-12 hours, the temperature is reduced to room temperature after the reaction is finished, after residual gas is exhausted, suction filtration is carried out, a small amount of acetone is washed, and drying is carried out to obtain 10.8g of white solid tazobactam 3, 5-dinitrobenzyl ester, and all indexes are in accordance with the regulations through liquid.
5) Deprotection of the amino acid
Taking 48.0g (0.1mol) of tazobactam 3, 5-dinitrobenzyl ester, transferring the tazobactam into a 1000mL three-necked bottle, adding 300mL of dichloromethane, adding 1.0g of palladium carbon, controlling the temperature to be 20-30 ℃, and introducing hydrogen to react for 3-4 hours (monitoring the reaction degree by TLC, developing agent V ethyl acetate: V n-hexane ═ 1: 4). After the reaction is finished, adding 200mL of water and 10.0g of sodium bicarbonate, stirring for 30 minutes, demixing, adding activated carbon into a water layer for decoloring, adding hydrochloric acid for acidification, filtering, washing with water, and drying to obtain 28.3g of white solid tazobactam acid with the yield of 94.2%.
6) Preparation of 3, 5-dinitrobenzyl chloride from byproduct 3, 5-dinitrotoluene
And (3) carrying out reduced pressure distillation on the dichloromethane layer obtained in the step 2) to obtain 16.0g of 3, 5-dinitrotoluene oily matter, adding 100g of acetone, adding 13.4g (0.1mol) of N-chlorosuccinimide, controlling the temperature of 25-35 ℃ to react for 5-6 hours, adding 100g of N-hexane, stirring for 1-2 hours, carrying out suction filtration, washing with a small amount of N-hexane, and drying to obtain 19.3g of solid with the yield of 89.0%.
Example 2: esterification reaction
29.6g (0.1mol) of bromosulfoxylic acid was taken, transferred into a 500mL three-necked flask, added with 100g of acetone, added with 23.8g (0.11mol) of 3, 5-dinitrobenzyl chloride prepared in step 6) of example 1, 9.2g of sodium bicarbonate, and reacted at a temperature of 35 to 40 ℃ for 4 to 6 hours (the degree of reaction was monitored by TLC, developing agent V ethyl acetate: v n-hexane ═ 1: 2). After the reaction is finished, 200g of water is added, stirred for 1-2 hours, filtered, washed and dried to obtain 45.7g of solid with the yield of 96.0%.
Example 3: deprotection reaction
48.0g (0.1mol) of tazobactam 3, 5-dinitrobenzyl ester, which is the intermediate synthesized in example 1, is taken out and transferred into a 1000mL three-necked flask, 300mL of dichloromethane and 1.1g of palladium carbon are added, and hydrogen gas is introduced for reaction for 3-4 hours at the temperature of 25-30 ℃ (the reaction degree is monitored by TLC, a developing agent V ethyl acetate: V n-hexane is 1: 4). After the reaction is finished, adding 200mL of water and 10.0g of sodium bicarbonate, stirring for 30 minutes, demixing, adding activated carbon into a water layer for decoloring, adding hydrochloric acid for acidification, filtering, washing with water, and drying to obtain 28.0g of white solid tazobactam acid with the yield of 93.2%.
Example 4: preparation of 3, 5-dinitrobenzyl chloride from byproduct 3, 5-dinitrotoluene
Taking the dichloromethane layer after the layering in the example 3, carrying out reduced pressure distillation to obtain 15.5g of 3, 5-dinitrotoluene oily matter, adding 100g of acetone, adding 13.4g (0.1mol) of N-chlorosuccinimide, controlling the temperature of 25-35 ℃ to react for 7-8 hours, adding 100g of N-hexane, stirring for 1-2 hours, carrying out suction filtration, washing with a small amount of N-hexane, drying to obtain 19.7g of solid, wherein the yield is 91.2%.
Example 5: esterification reaction
29.6g (0.1mol) of bromosulfoxylic acid was taken, transferred into a 500mL three-necked flask, added with 100g of acetone, added with 23.4g (0.108mol) of 3, 5-dinitrobenzyl chloride prepared in step 6) of example 1, 9.2g of sodium bicarbonate, and reacted for 4 to 6 hours while controlling the temperature at 30 to 35 ℃ (the degree of reaction was monitored by TLC, developing agent V ethyl acetate: v n-hexane ═ 1: 2). After the reaction is finished, 200g of water is added, stirred for 1-2 hours, filtered, washed and dried to obtain 45.5g of solid with the yield of 95.6 percent.
Example 6: deprotection reaction
48.0g (0.1mol) of tazobactam 3, 5-dinitrobenzyl ester, an intermediate synthesized in example 1, was transferred into a 1000mL three-necked flask, 300mL of methylene chloride was added, 0.95g of palladium on charcoal was added, and the reaction was carried out by introducing hydrogen gas at 20 to 25 ℃ for 3 to 4 hours (the degree of reaction was monitored by TLC, a developing agent V ethyl acetate: V n-hexane: 1: 4). After the reaction is finished, adding 200mL of water and 10.0g of sodium bicarbonate, stirring for 30 minutes, layering, adding a certain amount of activated carbon into a water layer for decoloring, adding hydrochloric acid for acidification, performing suction filtration, washing with water, and drying to obtain 28.1g of white solid tazobactam acid with the yield of 93.5%.
Example 7: preparation of 3, 5-dinitrobenzyl chloride from byproduct 3, 5-dinitrotoluene
Taking the dichloromethane layer after the layering in the embodiment 6, carrying out reduced pressure distillation to obtain 14.0g of p-nitrotoluene oily matter, adding 100g of acetone, adding 13.4g (0.1mol) of N-chlorosuccinimide, controlling the temperature to be 25-30 ℃ to react for 5-6 hours, adding 100g of N-hexane, stirring for 1-2 hours, carrying out suction filtration, washing with a small amount of N-hexane, and drying to obtain 20.0g of solid with the yield of 92.1%.
Claims (3)
1. A preparation method of tazobactam takes 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide as a raw material, and is characterized in that the raw material is subjected to esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition and deprotection steps in sequence,
the esterification reaction is that 3, 5-dinitrobenzyl chloride is used as a carboxyl protection reagent to react with 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide, 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide and 3, 5-dinitrobenzyl chloride are added into an acetone solvent, sodium bicarbonate is added, the temperature is controlled to be 30-40 ℃ for reaction for 4-6 hours, and after the esterification reaction, 3, 5-dinitrobenzyl ester is obtained through post-treatment, and after the esterification reaction, tazobactam 3, 5-dinitrobenzyl ester is obtained through further reduction, thermal cracking, chloromethylation, azidation, double oxidation and cycloaddition;
the deprotection reaction is as follows: adding tazobactam 3, 5-dinitrobenzyl ester into dichloromethane serving as a solvent, adding palladium carbon, controlling the temperature to be 20-30 ℃, and introducing hydrogen to react for 3-4 hours; after the reaction is finished, adding a sodium bicarbonate solution, stirring, layering into a water layer and a dichloromethane layer, decoloring the water layer, adding hydrochloric acid, acidifying to separate out a product, performing suction filtration, washing with water, and drying to obtain tazobactam; the byproduct 3, 5-dinitrotoluene reacts with chlorinated reagent N-chlorosuccinimide to prepare 3, 5-dinitrobenzyl chloride for recycling.
2. The method for preparing tazobactam, according to claim 1, wherein the solvent used in the reaction of the byproduct 3, 5-dinitrotoluene with N-chlorosuccinimide is DMF, acetone or acetonitrile, and the reaction temperature is 20-40 ℃.
3. The method for preparing tazobactam as claimed in claim 2, wherein the preparation of 3, 5-dinitrobenzyl chloride from the byproduct 3, 5-dinitrotoluene comprises the following steps: and (3) taking a dichloromethane layer subjected to deprotection reaction, carrying out reduced pressure distillation to obtain a p-3, 5-dinitrotoluene oily substance, then adding acetone, adding N-chlorosuccinimide, reacting for 5-6 hours at the temperature of 25-35 ℃, and carrying out aftertreatment to obtain 3, 5-dinitrobenzyl chloride.
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