CN109651399B - Preparation method of tazobactam - Google Patents
Preparation method of tazobactam Download PDFInfo
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- CN109651399B CN109651399B CN201910094506.6A CN201910094506A CN109651399B CN 109651399 B CN109651399 B CN 109651399B CN 201910094506 A CN201910094506 A CN 201910094506A CN 109651399 B CN109651399 B CN 109651399B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/08—Modification of a carboxyl radical directly attached in position 2, e.g. esterification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of tazobactam, which takes 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide as a raw material, and sequentially carries out esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition and deprotection steps to obtain tazobactam.
Description
Technical Field
The invention relates to a preparation method of tazobactam, belonging to the technical field of chemical synthesis medicines.
Background
Tazobactam is a novel penicillane sulfone β -lactamase inhibitor developed by the pharmaceutical company of Japanese Roc, is one of β -lactamase inhibitors with the best clinical application effect at present, has the characteristics of high stability, low activity, low toxicity, strong enzyme inhibition activity and the like, and has the structural formula as follows:
when the tazobactam sodium and the piperacillin sodium are used together, an obvious synergistic effect is generated, the tazobactam sodium and piperacillin sodium compound preparation is widely used for treating serious systemic and local infection, abdominal cavity infection, lower respiratory tract infection, soft tissue infection, septicemia and the like, has wider antibacterial spectrum and indications compared with other currently used antibacterial compound preparations, and overcomes drug resistance to show great advantages.
At present, most manufacturers take 6-APA as a raw material and prepare the tazobactam by the steps of bromination, oxidation, esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition, deprotection and the like in sequence, and a reaction equation is shown as follows.
In the above synthetic route, the protection of carboxyl group in the third esterification reaction is very important to the whole reaction process. At present, most tazobactam synthesis processes adopt diphenyl diazomethane for protection. Methods for synthesizing diphenyldiazomethane have been reported in the literature, such as mercury oxide method, electrolytic manganese dioxide method, chloramine-T method, and peroxyacetic acid method. Because the mercury oxide method and the manganese dioxide electrolysis method have larger environmental pollution and the chloramine-T method has higher cost, the diazo-methane is prepared by adopting the peroxyacetic acid method in the industrial mass production at present, and the equation is as follows:
however, the peroxyacetic acid method for preparing the diphenyl diazomethane has the following disadvantages:
(1) peroxyacetic acid is extremely unstable in property, is violently decomposed and even explodes when being heated, and is a great hidden danger in the production and storage processes.
(2) Peracetic acid has a certain toxicity and a very strong corrosiveness, has a strong irritation to the skin and eyes, can cause severe burns to the skin, can cause irreversible damage or even blindness by direct contact of the eyes with liquids, can be fatal when swallowed, and can cause irritation and damage to the respiratory tract by the inhalation of vapors therefrom.
(3) The preparation of peroxyacetic acid requires acetic acid, acetic acid is also generated in the preparation process, the acetic acid contains carboxyl, and the generated diphenyl diazomethane can react with the carboxyl of the acetic acid to generate a large amount of byproducts, and the reaction equation is shown as follows. Resulting in poor product quality and low yield (TLC detection during the reaction, producing a relatively large impurity, which was confirmed to be produced by the reaction of the diazomethane and acetic acid).
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of tazobactam. The method adopts benzyl bromide as a protective group of carboxylic acid group, and then uses hydrogenolysis reaction to remove the benzyl protection. Compared with the existing process route, the provided method for protecting and removing the carboxyl has the advantages of simple flow, environmental protection, low by-product and the like.
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 that acetone is used as a solvent, benzyl bromide is used as a carboxyl protection reagent to react with 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide (compound 1) in the presence of sodium bicarbonate to obtain 6 α -bromine penam-3 α -carboxylic acid benzyl ester-1 β -oxide (compound 2), and the esterification reaction is further subjected to reduction, thermal cracking, chloromethylation, azidation, double oxidation and cycloaddition to obtain tazobactam benzyl ester (compound 8);
the deprotection reaction is as follows: palladium carbon is used as a catalyst, and benzyl protection of tazobactam benzyl ester (compound 8) is removed by hydrogen to obtain tazobactam.
The reaction equation is as follows:
in the esterification reaction, the mass ratio of the 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide to the benzyl bromide and the sodium bicarbonate is 1: 1.8-2.5: 0.4-0.6.
The adding amount of the palladium-carbon catalyst for deprotection reaction is 0.005-0.03 time of the mass of tazobactam benzyl ester.
Preferably, the esterification reaction step specifically comprises the steps of adding 6 α -bromopenam-3 α -carboxylic acid-1 β -oxide into acetone, slowly adding liquid benzyl bromide, adding sodium bicarbonate after the addition is finished, carrying out heat preservation reaction at normal temperature, washing a reaction solution after the reaction is finished, reducing pressure and evaporating to dryness, adding toluene for pulping, cooling to 0-5 ℃, carrying out suction filtration, and drying to obtain 6 α -bromopenam-3 α -carboxylic acid benzyl ester-1 β -oxide.
Preferably, the deprotection reaction comprises the following specific steps: (1) adding tazobactam benzyl ester into a reactor by using ethanol as a solvent, and adding a palladium-carbon catalyst; (2) vacuumizing, replacing air with nitrogen for 3 times, replacing nitrogen with hydrogen for 3 times after nitrogen is exhausted, and reacting at normal temperature for 1-2h after replacement is finished; (3) after the reaction is finished, filtering out the palladium-carbon by suction filtration; (4) cooling and crystallizing the filtrate at-2-2 ℃ for 1-1.5h, and performing suction filtration to obtain a crude tazobactam product.
Further, the crude tazobactam product is recrystallized by using a mixed solvent of ethanol and purified water (the volume ratio of the ethanol to the purified water is 1.5-2.5: 1) to obtain tazobactam.
The present invention uses benzyl bromide as a protecting group for the carboxylic acid group, which was found to occur readily under basic conditions, and we introduced sodium bicarbonate. The removal of benzyl protection is relatively simple and can be achieved by hydrogenolysis of palladium on carbon. Compared with the method for preparing the diphenyl diazomethane (diphenyl hydrazone and dangerous peroxyacetic acid are used as raw materials), the method has the advantages of simple raw materials and easy preparation. Compared with the existing process route, the provided method for protecting and removing the carboxyl has the advantages of simple flow, environmental protection, low by-product and the like.
Detailed Description
The invention will be further illustrated with reference to specific examples, without limiting the scope of protection of the patent.
Example 1:
(1) esterification
Adding 50g of 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide into 250g of acetone, slowly adding 100g of liquid benzyl bromide, adding 25g of sodium bicarbonate after the addition is finished, starting stirring, keeping the temperature at normal temperature for reaction for 24h, adding 120ml of saturated sodium bicarbonate solution after the heat preservation is finished, washing, layering, adding 80ml of purified water for washing, layering, evaporating an organic layer under reduced pressure, adding 50ml of toluene for pulping for 0.5-2h, cooling to 0-5 ℃, performing suction filtration and drying to obtain 63.9g of white solid 6 α -bromine penam-3 α -carboxylic acid benzyl ester-1 β -oxide, wherein the yield is 98.0%.
(2) Reduction of
Adding 240g of tetrahydrofuran into a reactor, adding 6 α -bromine penam-3 α -carboxylic acid benzyl ester-1 β -oxide, adding 100g of purified water, adding 30g of ammonium acetate, controlling the temperature to be 0-10 ℃, adding 15.0g of zinc powder in batches, keeping the temperature for reaction for 2-3 hours, performing suction filtration, discarding a water layer, evaporating a tetrahydrofuran layer under reduced pressure, adding 100ml of toluene for recrystallization, performing suction filtration and drying to obtain 49.4g of white solid 6, 6-dihydro penam-3 α -carboxylic acid benzyl ester-1 β -oxide, wherein the yield is 95.2%.
(3) Thermal cracking, chloromethylation, azidation
Adding 600ml of toluene into the 6, 6-dihydropenam-3 α -benzyl carboxylate-1 β -oxide obtained in the previous step for dissolution, adding 29.4g of dimercapto benzothiazole, heating and refluxing for 6 hours for cracking reaction, cooling after the refluxing is finished, and detecting by liquid chromatography to obtain a qualified thermal cracking reaction solution;
evaporating toluene to dryness under reduced pressure, adding 800mL dichloromethane for dissolution, adding 400mL industrial concentrated hydrochloric acid, cooling to-15-10 ℃, dropwise adding a sodium nitrite solution (15g sodium nitrite +100mL water), reacting for 12h after dropwise adding, filtering for layering, adding 200mL saturated sodium bicarbonate solution into an organic phase for washing, layering, and adding 200mL tap water for washing and layering;
evaporating dichloromethane to dryness under reduced pressure, adding 380ml of DMF reagent for dissolving, slowly dropwise adding 200g of saturated sodium azide solution (35.0g is dissolved in 165g of DMF), keeping the temperature at 30-40 ℃ for 8 hours after the dropwise adding is finished, adding 500ml of ethyl acetate for extraction after the temperature keeping is finished, adding 200ml of purified water for washing twice for layering, and distilling under reduced pressure until the oily matter is dried to obtain an oily matter which is qualified through liquid chromatography detection.
(4) Double oxidation, cycloaddition
Adding 200mL of glacial acetic acid to dissolve the oily matter, controlling the temperature to be 20-30 ℃, adding 50g of potassium permanganate to react, preserving the temperature for 2h after the addition is finished, and dropwise adding 80g of hydrogen peroxide to continue the reaction. Adding 400ml of saturated sodium bicarbonate solution for washing, layering, adding 400ml of purified water for washing and layering; distilling under reduced pressure until the solid is dry, adding 300mL of acetone for dissolution, pumping the feed liquid into a high-pressure kettle, introducing acetylene for cyclization reaction, controlling the temperature to be 80-90 ℃ and the pressure to be 0.10-0.15MPa, reacting for 10-15 hours, cooling to room temperature after heat preservation, draining residual gas, performing suction filtration and drying to obtain 20.4g of white solid tazobactam benzyl ester, and detecting that all indexes meet the requirements through liquid chromatography.
(5) Deprotection of the amino acid
Dissolving 10g of tazobactam benzyl ester in 300g of absolute ethyl alcohol, putting 0.2g of palladium-carbon catalyst into a three-mouth reaction bottle, starting stirring, vacuumizing by using a vacuum pump until P is less than or equal to-0.05 MPa, introducing nitrogen to replace the air in the kettle, and repeatedly replacing for 3 times; and (3) after nitrogen is exhausted, vacuumizing by using a vacuum pump until the pressure P is less than or equal to-0.05 MPa, then introducing hydrogen to replace the nitrogen, repeatedly replacing for 3 times, exhausting the hydrogen after replacement is finished, sealing a reaction bottle, carrying out catalytic hydrogenolysis reaction, keeping the temperature for 1.5 hours after stabilization, taking out reaction liquid after the time is finished, carrying out suction filtration to separate out the palladium-carbon catalyst, transferring filtrate into a three-neck flask, cooling and crystallizing for 90min at the temperature of-2-2 ℃, carrying out suction filtration, and drying to obtain 7.4g of white solid. Yield: 96.19 percent.
(6) Refining
Adding 34.6g of ethanol into a 250ml three-neck flask, adding 19.2g of purified water, heating to 45 ℃, adding 7.0g of crude tazobactam, stirring for 30min, stopping heating, transferring the system into cooling liquid circulating hydrazine, preserving heat at-5 ℃ for 24h, preserving heat, and performing suction filtration to obtain 6.5g of white solid tazobactam. The solid is analyzed by liquid chromatography, and all indexes of the solid meet the requirements (the purity is 99.83%).
Example 2: esterification
100g of 6 α -bromopenam-3 α -carboxylic acid-1 β -oxide is put into a reaction bottle, 500g of acetone, 210g of liquid benzyl bromide and 45g of sodium bicarbonate are sequentially added, stirring is started and the reaction is carried out at normal temperature for 24 hours, 240ml of saturated sodium bicarbonate solution is added after the temperature preservation is finished for washing and layering, 160ml of purified water is added for washing and layering, the organic layer is evaporated to dryness under reduced pressure, 100ml of toluene is added for pulping for 0.5-2 hours, the temperature is reduced to 0-5 ℃ after the pulping is finished, suction filtration and drying are carried out, and 128.3g of white solid 6 α -bromopenam-3 α -benzyl carboxylate-1 β -oxide is obtained, wherein the yield is 98.34%.
Example 3: deprotection of the amino acid
Putting 16g of tazobactam benzyl ester into a reaction bottle, adding 480g of absolute ethyl alcohol, putting 0.32g of palladium-carbon catalyst into the three-mouth reaction bottle, starting stirring, vacuumizing by using a vacuum pump until the pressure P is less than or equal to-0.05 MPa, introducing nitrogen to replace the air in the kettle, and repeatedly replacing for 3 times; and (3) after nitrogen is exhausted, vacuumizing by using a vacuum pump until the pressure P is less than or equal to-0.05 MPa, then introducing hydrogen to replace the nitrogen, repeatedly replacing for 3 times, exhausting the hydrogen after replacement is finished, sealing a reaction bottle, carrying out catalytic hydrogenolysis reaction, keeping the temperature for 2 hours after stabilization, taking out reaction liquid after the time is finished, carrying out suction filtration to separate out the catalyst, transferring filtrate into a three-neck flask, cooling and crystallizing for 90min at the temperature of-2-2 ℃, carrying out suction filtration, and drying to obtain 11.8g of white solid. Yield: 95.8 percent.
Claims (4)
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 comprises the steps of adding 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide into acetone, slowly adding liquid benzyl bromide, adding sodium bicarbonate after the addition, keeping the temperature at normal temperature for reaction, washing a reaction solution after the reaction is finished, drying by distillation under reduced pressure, adding toluene for pulping, cooling to 0-5 ℃, carrying out suction filtration, and drying to obtain 6 α -bromine penam-3 α -carboxylic acid benzyl ester-1 β -oxide, wherein the mass ratio of the 6 α -bromine penam-3 α -carboxylic acid-1 β -oxide to benzyl bromide and sodium bicarbonate is 1: 1.8-2.5: 0.4-0.6;
after esterification, further carrying out reduction, thermal cracking, chloromethylation, azidation, double oxidation and cycloaddition to obtain tazobactam benzyl ester;
the deprotection reaction is as follows: (1) adding tazobactam benzyl ester into a reactor by using ethanol as a solvent, and adding a palladium-carbon catalyst; (2) vacuumizing, replacing air with nitrogen for at least 2 times, replacing nitrogen with hydrogen for at least 2 times after nitrogen is exhausted, and reacting at normal temperature for 1-2h after replacement is finished; (3) after the reaction is finished, filtering out the palladium-carbon by suction filtration; (4) cooling and crystallizing the filtrate at-2-2 ℃ for 1.5h, and performing suction filtration to obtain a crude tazobactam product.
2. The method according to claim 1, wherein the amount of palladium-on-carbon catalyst added for the deprotection reaction is 0.005 to 0.03 times the amount of tazobactam benzyl ester.
3. The method for preparing tazobactam, as claimed in claim 1, wherein the crude tazobactam is recrystallized from a mixed solvent of ethanol and purified water to obtain tazobactam.
4. The method for preparing tazobactam according to claim 3, wherein the volume ratio of the ethanol to the purified water is 1.5-2.5: 1.
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