CN113666946B - Preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam - Google Patents
Preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam Download PDFInfo
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- 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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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- 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
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- C07D499/06—Preparation by forming the ring or condensed ring systems
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Abstract
The invention provides a preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, a tazobactam intermediate and tazobactam. The preparation method comprises the following steps: reacting reaction raw materials comprising a disulfide ring-opening compound, 1,2, 3-triazole and a first oxidant in a first solvent to obtain a product system comprising 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, wherein the structural formula of the disulfide ring-opening compound is shown in the specification
The structural formula of the 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is shown in the specification
Description
Technical Field
The invention relates to the technical field of tazobactam preparation, and particularly relates to a preparation method of 2 beta-tolylpenicillanic acid diphenylmethyl ester, a tazobactam intermediate and tazobactam.
Background
Clinical studies have shown that, with the widespread use of antibiotics, pathogens are becoming increasingly resistant to antibiotics, and the clinical efficacy of antibiotics is far from before. In order to solve the problem of drug resistance, a great deal of research is carried out on the drug resistance of BLA inhibitors represented by tazobactam, and great breakthrough is made. The in vivo and in vitro experiments of the medicine combined with ampicillin, amoxicillin, piperacillin and the like all achieve more satisfactory effects.
The chemical name of tazobactam is: (2S, 3S, 5R) -3-methyl-7-oxo-3- (1H-1, 2, 3-triazolylmethyl) -4-thioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4, 4-dioxide. The structure is as follows:
tazobactam is a novel beta-lactam antibiotic of penicillanic acids developed by the pharmaceutical company of Japan Roc, and is a currently accepted beta-lactamase inhibitor with the widest antibacterial spectrum, the best resistance, the best clinical application effect and the most promising prospect. The compound tazobactam preparation has good curative effect on infection of abdominal cavity, respiratory tract, urinary tract, skin tissue and the like, and has obvious curative effect on paediatrics, burns, hematopathy and the like. Due to the excellent performance of tazobactam, the research on the synthesis and clinical application of tazobactam is active at home and abroad at present, and the synthesis route and the process of tazobactam are continuously perfected. However, the synthesis technology is complicated due to the long synthesis steps, and is still a hot point of synthesis research.
At the present stage, the synthetic routes of tazobactam are mainly divided into two categories: one is cyclized after azide and the other is directly linked to the side chain triazole ring. The detailed description is as follows:
(mono) azide substituted chloride route
The method uses 6, 6-dihydropenam sulphoxide acid diphenylmethyl ester as a raw material, and the tazobactam is obtained by condensation, chlorination, azido group addition, oxidation, cyclization and deprotection. The literature (Synthesis, 1986, 292-. In particular, in the Step-3 Step, the ratio of the five-membered ring product to the six-membered ring isomer is as high as 3: 2, the selectivity is poor, so that the yield of the reaction in the Step is low, and the products of Step-2 and Step-3 are unstable, and the scale-up production is difficult. Potassium permanganate is generally used as an oxidant in the Step-4 oxidation reaction, but the three-waste environmental pollution caused by a byproduct manganese salt is large, which does not meet the future development direction of green chemistry, flammable and explosive acetylene gas is required in the Click 1, 3-dipolar cycloaddition reaction of Step-5, and a large safety risk exists in the production process. The API of Step-6 uses m-methylphenol as a solvent for deprotection to obtain a final product tazobactam, wherein the m-methylphenol not only causes large amount of three wastes in the post-treatment process, but also causes drug genotoxicity due to trace amount of m-methylphenol residue in the product.
Therefore, although the materials used in the route are cheap and easy to obtain, the route has the disadvantages of multiple reaction steps, poor reaction selectivity of key steps, low total reaction yield and serious environmental pollution, and flammable, explosive and highly toxic materials are used, so that the safety risk is high, and the route does not accord with the development direction of the modern pharmaceutical industry.
(di) direct triazole substitution route
The method also uses 6, 6-dihydropenam sulphoxide acid diphenylmethyl ester as a raw material, and the difference is that a process of preparing triazole after substitution by azide is replaced by a triazole substituted chloride, so that the selectivity of five-membered ring and six-membered ring in substitution reaction can be improved, and the problem of instability of azide substitution products is solved. However, the chloride ion of 2 β -chloromethyl penicillanic acid diphenylmethyl ester is easy to leave due to the influence of sulfur atom lone pair electrons, so that the stability of the chloride intermediate is poor, and meanwhile, the nucleophilicity of triazole is lower than that of sodium azide, so that the reaction rate is slow and the yield is low. Chinese patent applications with patent application publication numbers CN104031065A and CN109305977A respectively report that the stability of sulfur atoms is increased by performing single oxidation to sulfoxide or double oxidation to sulfone, but the activity of chlorine atoms is deteriorated, so that part of triazole cannot perform nucleophilic attack, and the reaction yield is greatly reduced.
In conclusion, the existing tazobactam synthesis process has the disadvantages of long route, complex synthesis technology, more byproducts, low yield and serious environmental pollution, and no satisfactory result is obtained for the improvement of the tazobactam synthesis process, so that the development of a route which has the advantages of short step, high yield, environmental friendliness and suitability for industrial scale-up production is of great significance.
Disclosure of Invention
The invention mainly aims to provide a preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, a tazobactam intermediate and tazobactam, and aims to solve the problem of low yield of a method for synthesizing tazobactam in the prior art.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing 2 β -tolylpenicillanic acid diphenylmethyl ester, comprising: reacting reaction raw materials comprising a disulfide ring-opening compound, 1,2, 3-triazole and a first oxidant in a first solvent to obtain a product system comprising 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, wherein the structural formula of the disulfide ring-opening compound is shown in the specification
The structural formula of the 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is shown in the specification
。
Further, the first oxidant is one or more selected from the group consisting of ceric ammonium nitrate, iodobenzene acetate, ammonium persulfate, 5 to 50wt% hydrogen peroxide, t-butyl hydroperoxide, potassium persulfate, potassium monopersulfate, carbamide peroxide, and cumene hydroperoxide.
Furthermore, the molar ratio of the 1,2, 3-triazole to the first oxidant is 1-20: 1.
Further, the molar ratio of the 1,2, 3-triazole to the disulfide ring-opening compound is 2-20: 1.
further, the reaction temperature is 20-50 ℃, and the reaction time is 2-48 h.
Further, the mass ratio of the volume of the first solvent to the disulfur ring-opening compound is 5-50 mL:1g, the first solvent is selected from any one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, trichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol and hexafluoroisopropanol.
Further, a first additive for promoting the reaction is added, and the molar ratio of the first additive to the sulfur ring-opening compound is 0.05-1: 1, the first additive is selected from one or more of acetic acid, hydrochloric acid, phosphoric acid, hypoboric acid, phenylboronic acid, hexafluoroisopropanol, triethylamine, diisopropylethylamine, triphenylphosphine, 1 '-binaphthyl-2, 2' -diphenylphosphine, aluminum oxide and silver nitrate.
According to another aspect of the present invention, there is provided a method for preparing a tazobactam intermediate, the tazobactam intermediate having the structural formula:
the preparation method comprises the following steps: step S1, preparing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester by adopting the preparation method; and step S2, carrying out oxidation reaction on 2 beta-tolylpenicillanic acid diphenylmethyl ester under the action of a second oxidant and a first catalyst to obtain a tazobactam intermediate.
The second oxidant is one or more selected from potassium permanganate, 5-50 wt% hydrogen peroxide, tert-butyl hydroperoxide, ammonium persulfate, potassium peroxymonosulfonate, carbamide peroxide and cumene hydroperoxide, and the feeding amount of the second oxidant is 2-10 equivalent.
The first catalyst is one or more selected from sodium tungstate, tungstic acid and rhenium trioxide, and the dosage of the first catalyst is 0.01-0.2 equivalent.
Further, the temperature of the oxidation reaction is 20-60 ℃, and the time of the oxidation reaction is 1-24 hours.
Further, a second additive for promoting the oxidation reaction is added, wherein the amount of the second additive is 0.1-1 equivalent, and the second additive is one or more selected from phosphoric acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid.
Further, the oxidation reaction is carried out in a second solvent, wherein the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, trichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol and hexafluoroisopropanol, and the mass ratio of the volume of the second solvent to the 2 beta-tolylmethyl trisazolecarboxylate is 5-20 mL:1 g.
According to still another aspect of the present invention, there is provided a method for preparing tazobactam, the method comprising: step S1, preparing a tazobactam intermediate by the aforementioned preparation method; and step S2, carrying out deprotection on the tazobactam intermediate to prepare tazobactam.
Further, the step S2 includes: and carrying out deprotection reaction on the tazobactam intermediate under the action of hydrogen and a second catalyst to obtain tazobactam.
Furthermore, the feeding amount of the second catalyst is 5-20 wt% of the tazobactam intermediate, and the second catalyst is selected from Pd/C, Rh/C, Pd/Al2O3Any one or more of them.
Furthermore, the temperature of the deprotection reaction is 20-90 ℃, and the time of the deprotection reaction is 1-24 h.
Further, the deprotection reaction is carried out in a third solvent, the third solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol and hexafluoroisopropanol, and the mass ratio of the volume of the third solvent to the tazobactam intermediate is 5-20 mL:1 g.
By applying the technical scheme of the invention, the 1,2, 3-triazole is used for directly closing the ring of the disulfide ring-opened compound under the action of the first oxidant, so that a chloro-compound intermediate with poor stability is avoided, and the high-efficiency and high-selectivity synthesis of the disulfide ring-opened compound directly to the key intermediate 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is successfully realized. Compared with the current route for industrially producing 2 beta-tolylpenicillanic acid diphenylmethyl ester, the strategy not only shortens the reaction step, but also greatly improves the selectivity of the target product 2 beta-tolylpenicillanic acid diphenylmethyl ester, thereby obviously improving the reaction yield of the 2 beta-tolylpenicillanic acid diphenylmethyl ester, and further, the 2 beta-tolylpenicillanic acid diphenylmethyl ester is used as a key intermediate for synthesizing tazobactam, so that the yield of tazobactam is improved, and the cost is reduced.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As analyzed by the background technology, the method for synthesizing tazobactam in the prior art has the problem of low yield, and in order to solve the problem, the invention provides a preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, a tazobactam intermediate and tazobactam.
In an exemplary embodiment of the present application, there is provided a method for preparing 2 β -tolylpenicillanic acid diphenylmethyl ester, the method comprising: reacting reaction raw materials comprising a disulfide ring-opening compound, 1,2, 3-triazole and a first oxidant in a first solvent to obtain a product system comprising 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, wherein the structural formula of the disulfide ring-opening compound is shown in the specification
The structural formula of the 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is shown in the specification
。
Under the action of a first oxidant, 1,2, 3-triazole is used for directly closing a disulfide ring-opening compound, so that a chloride intermediate with poor stability is avoided, and the high-efficiency and high-selectivity synthesis of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester from the disulfide ring-opening compound directly to a key intermediate is successfully realized. Compared with the current route for industrially producing 2 beta-tolylpenicillanic acid diphenylmethyl ester, the strategy not only shortens the reaction step, but also greatly improves the selectivity of the target product 2 beta-tolylpenicillanic acid diphenylmethyl ester, thereby obviously improving the reaction yield of the 2 beta-tolylpenicillanic acid diphenylmethyl ester, and further, the 2 beta-tolylpenicillanic acid diphenylmethyl ester is used as a key intermediate for synthesizing tazobactam, so that the yield of tazobactam is improved, and the cost is reduced.
In an embodiment of the present application, the first oxidizing agent is one or more selected from the group consisting of cerium ammonium nitrate, iodobenzene acetate, ammonium persulfate, 5 to 50wt% hydrogen peroxide, tert-butyl hydroperoxide, potassium persulfate, potassium monopersulfate, carbamide peroxide, and cumene hydroperoxide.
The first oxidant is used for oxidizing and breaking a disulfide bond of a disulfide ring-opening compound to obtain a sulfur free radical, the sulfur free radical attacks a double bond and closes a ring to obtain a sulfonium ion intermediate of a three-membered ring, and then 1,2, 3-triazole attacks the sulfonium ion intermediate and closes the ring to obtain a standard product 2 beta-triazole methyl penicillanic acid diphenylmethyl ester, and the first oxidant can improve the efficiency of the ring closing reaction.
In order to improve the synergistic effect of the first oxidant and the 1,2, 3-triazole and accelerate the ring closing reaction efficiency of the 1,2, 3-triazole and the disulfide ring-opening compound, the molar ratio of the 1,2, 3-triazole to the first oxidant is preferably 1-20: 1.
In order to increase the yield of 2 beta-tolylmethyl penicillanic acid diphenylmethyl ester by carrying out triazole treatment on the disulfide ring-opening compound as much as possible, the molar ratio of 1,2, 3-triazole to the disulfide ring-opening compound is preferably 2-20: 1, preferably 8-15: 1.
in an embodiment of the present invention, the reaction temperature is 20 to 50 ℃, the reaction time is 2 to 48 hours, preferably the reaction temperature is 25 to 40 ℃, and the reaction time is 15 to 24 hours.
The reaction temperature affects the breakage of chemical bonds of reactants and the bonding efficiency of new chemical bonds in products, and the overall efficiency of the reaction can be improved within the reaction temperature and time range, and the probability of side reactions is reduced as much as possible.
In one embodiment of the present application, the mass ratio of the volume of the first solvent to the disulfur ring-opening compound is 5 to 50 mL:1g, preferably 10-25 mL:1g, preferably the first solvent is selected from any one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, isopropanol, hexafluoroisopropanol.
The above-mentioned kind of solvent is advantageous for improving the solubility of each of the above-mentioned reaction raw materials therein, so that each of the reaction raw material molecules is dispersed more uniformly in the solvent, the probability of contact and collision of the reaction raw material molecules by the solvent medium is higher, and further, the efficiency of the reaction is improved, and further, it is preferable that the ratio of the volume of the solvent to the mass of the disulfide ring-opening compound is within the above-mentioned range, so that the efficiency of the reaction is improved.
In one embodiment of the present application, a first additive for promoting the above reaction is added, and the molar ratio of the first additive to the disulfur ring-opening compound is 0.05 to 1:1, preferably 0.2-0.8: 1, preferably the first additive is selected from any one or more of acetic acid, hydrochloric acid, phosphoric acid, hypoboric acid, phenylboronic acid, hexafluoroisopropanol, triethylamine, diisopropylethylamine, triphenylphosphine, 1 '-binaphthyl-2, 2' -diphenylphosphine, aluminium oxide and silver nitrate.
The first additive can improve the reaction efficiency, and the first additive of the above kind and the addition amount thereof are preferably controlled within the above range in the present application, so that the reaction can be more sufficiently promoted, the reaction efficiency can be improved, and the waste of the additive and the excessive additive remaining in the product system are not caused.
In another exemplary embodiment of the present application, there is provided a method for preparing a tazobactam intermediate having the structural formula:
the preparation method comprises the following steps: step S1, preparing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester by adopting the preparation method; and step S2, carrying out oxidation reaction on 2 beta-tolylpenicillanic acid diphenylmethyl ester under the action of a second oxidant and a first catalyst to obtain a tazobactam intermediate.
The preparation method is adopted, namely, under the action of the first oxidant, the 1,2, 3-triazole is used for directly closing the ring of the disulfide ring-opened compound, so that a chloro-compound intermediate with poor stability is avoided, the high-efficiency and high-selectivity synthesis from the disulfide ring-opened compound directly to the key intermediate 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is successfully realized, and on the basis, the selectivity and the yield of the tazobactam intermediate can be improved through the oxidation reaction.
In an embodiment of the present invention, the second oxidant is one or more selected from potassium permanganate, 5 to 50wt% hydrogen peroxide, tert-butyl hydroperoxide, ammonium persulfate, potassium peroxymonosulfonate, carbamide peroxide, and cumene hydroperoxide, and the feeding amount of the second oxidant is preferably 2 to 10 equivalents, and preferably 5 to 8 equivalents. The above-mentioned every oxidant has higher oxidizing power, can preferably adopt the above-mentioned other substances of second oxidant to substitute potassium permanganate that the three wastes are serious, have reached the same or even better oxidation effect, and the aftertreatment after the reaction is simple, accord with the development direction of the green chemistry better. The feeding amount of the second oxidant meets the requirement of oxidation reaction, and too much oxidant cannot be caused to cause too fast oxidation.
In some embodiments, the first catalyst is selected from any one or more of sodium tungstate, tungstic acid and rhenium trioxide, and the dosage of the first catalyst is preferably 0.01 to 0.2 equivalent, preferably 0.1 to 0.2 equivalent. The adoption of sodium tungstate and other catalysts is beneficial to improving the catalytic efficiency. The catalyst with the content has enough catalytic activity to promote the oxidation reaction, and the problems of cost increase and serious residue caused by excessive use of the catalyst are avoided.
In order to improve the efficiency of the oxidation reaction, the temperature of the oxidation reaction is preferably 20-60 ℃, the time of the oxidation reaction is preferably 1-24 hours, the temperature of the oxidation reaction is preferably 40-55 ℃, and the time of the oxidation reaction is preferably 3-20 hours.
In one embodiment of the present application, a second additive for promoting oxidation reaction is added, preferably in an amount of 0.1 to 1 equivalent, and preferably the second additive is selected from any one or more of phosphoric acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
The second additive is advantageously of the kind and amount described above in synergistic cooperation with the second oxidant and the first catalyst to increase the efficiency of the oxidation reaction.
In order to improve the efficiency of the oxidation reaction, the oxidation reaction is preferably performed in a second solvent, the second solvent is preferably selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, and hexafluoroisopropanol, and the mass ratio of the volume of the second solvent to 2 β -tolylpenicillanic acid diphenylmethyl ester is preferably 5-50 mL:1g, and more preferably 9mL:1 g.
In another exemplary embodiment of the present application, there is provided a method for preparing tazobactam, the method comprising: step S1, preparing a tazobactam intermediate by adopting the preparation method; and step S2, carrying out deprotection on the tazobactam intermediate to prepare tazobactam.
The preparation method is adopted, namely, under the action of the first oxidant, the 1,2, 3-triazole is used for directly closing the ring of the disulfide ring-opened compound, so that a chloro-compound intermediate with poor stability is avoided, and the high-efficiency and high-selectivity synthesis from the disulfide ring-opened compound directly to the key intermediate 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is successfully realized. Compared with the current route for industrially producing 2 beta-tolylpenicillanic acid diphenylmethyl ester, the strategy not only shortens the reaction step, but also greatly improves the selectivity of the target product 2 beta-tolylpenicillanic acid diphenylmethyl ester, thereby obviously improving the reaction yield of the tazobactam intermediate.
In an embodiment of the present application, the step S2 includes: and carrying out deprotection reaction on the tazobactam intermediate under the action of hydrogen and a second catalyst to obtain tazobactam.
The catalytic hydrogenation strategy is used for replacing the traditional m-methylphenol, so that the environmental pollution is reduced, the reaction yield is improved, and the production cost is reduced.
In order to improve the efficiency of the catalytic hydrogenation deprotection reaction, the feeding amount of the second catalyst is preferably 5-20 wt%, preferably 10-20 wt% of the tazobactam intermediate, and the second catalyst is preferably selected from Pd/C, Rh/C, Pd/Al2O3Any one or more of them.
In order to improve the efficiency of the deprotection reaction, the temperature of the deprotection reaction is preferably 20-90 ℃, the time of the deprotection reaction is 1-24 hours, the temperature of the deprotection reaction is preferably 60-90 ℃, and the time of the deprotection reaction is preferably 6-20 hours.
In order to improve the efficiency of the deprotection reaction, the deprotection reaction is preferably performed in a third solvent, and the third solvent is preferably selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, and hexafluoroisopropanol, and the mass ratio of the volume of the third solvent to the tazobactam intermediate is preferably 5 to 20mL:1g, and more preferably 9mL:1 g.
The advantageous effects of the present application will be described below with reference to specific examples and comparative examples.
Example 1
In a first step, the disulfide ring-opened compound 2 was prepared by the following route:
adding toluene (975 mL) into a four-mouth bottle provided with a water separator at room temperature, then sequentially adding 2-mercaptobenzothiazole (28.92 g, 172.90 mmol and 1.02 eq) and penicillanic sulfoxide acid diphenylmethyl ester 1(65 g, 169.51 mmol and 1.0 eq) into a system, then heating the system to 120 ℃, refluxing and dividing water for 2 hours, after the reaction of the raw materials is finished, rapidly cooling the system to room temperature, controlling the temperature to be 30-40 ℃, concentrating the product at High Performance Liquid Chromatography (HPLC) purity and the external standard yield of the system to 95%, and directly using the product for the next reaction after controlling the temperature to be 30-40 ℃ until no fraction is produced.
Secondly, preparing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester 3 by the following route:
dissolving the disulfide ring-opening compound 2 (about 90 g, 168.95mmol, 1.0 eq) prepared in the previous step in acetone (2250 mL) at room temperature, stirring for clarification, then sequentially adding 1,2, 3-triazole (116.64 g, 1689.48 mmol, 10.0 eq) and ceric amine nitrate (46.3 g, 844.74 mmol, 5.0 eq), keeping the temperature of the system at 28-33 ℃ and stirring for about 18h, after the raw materials react, gradually turbidity the system in the process, filtering to remove a bithiazole byproduct, quenching the excessive ceric amine nitrate in the filtrate by using 10wt% sodium bisulfite aqueous solution, adjusting the pH value to be neutral by using 10wt% sodium bicarbonate aqueous solution, concentrating the system at room temperature to remove acetone, extracting and separating the residual system by using dichloromethane, washing the organic phase by water to remove triazole, concentrating the residual organic phase to be free of distillate, crystallizing by using 2-methyltetrahydrofuran and n-heptane, the target product 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3 is obtained, and the two-step separation yield is 70%.
Nuclear magnetic hydrogen spectrum data of 2 beta-tolylmethyl penicillanic acid diphenylmethyl ester 3:1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 1.0 Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.48 – 7.25 (m, 10H), 6.91 (s, 1H), 5.41 (dd, J = 4.1, 1.7 Hz, 1H), 5.23 (s, 1H), 4.81 – 4.61 (m, 2H), 3.36 (s, 1H), 3.27 (dd, J = 16.3, 1.8 Hz, 1H), 1.11 (s, 3H)。
step three, preparing tazobactam diphenylmethyl ester 4 by the following route:
dissolving 2 beta-tolylmethyl penicillanic acid diphenylmethyl ester 3(50 g, 115.07 mmol) in acetonitrile (400 mL) and dichloromethane (50 mL) at room temperature, stirring for clarification, then sequentially adding sodium tungstate (3.80 g, 11.51 mmol, 0.1 eq), 85% phosphoric acid (1.33 g, 11.51 mmol, 0.1 eq), 98% sulfuric acid (2.30 g, 23.01 mmol, 0.2 eq) and 35% hydrogen peroxide (55.89 g, 575.36 mmol, 5.0 eq), heating the system to 55 ℃, continuing stirring for about 2 hours, after the reaction of the raw materials is finished, cooling the system to 20-30 ℃, concentrating under reduced pressure at the temperature to remove dichloromethane in the system, gradually turbidity the rest, continuing cooling the system to 15 ℃, then dropwise adding purified water (400 mL) into the system at the temperature, continuing cooling the system to 5 ℃, then preserving heat at the temperature, stirring for 2 hours, and filtering, and leaching the filter cake once with cold acetonitrile/purified water (1: 1, 50 mL), leaching with purified water (50 mL), and blow-drying the filter cake with nitrogen at room temperature to obtain tazobactam diphenylmethyl ester 4 with the HPLC purity of 99% and the separation yield of 90%.
Nuclear magnetic hydrogen spectrum data of tazobactam diphenylmethyl ester 4: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 1.1 Hz, 1H), 7.56-7.27 (m, 10H), 6.99 (s, 1H), 5.33-5.23 (m, 3H), 4.96 (d, J = 15.4 Hz, 1H), 3.37-3.29 (m, 2H), 1.13 (s, 3H).
Fourthly, preparing tazobactam by the following route:
adding methanol (960 mL) into a stainless steel high-pressure autoclave with the volume of 2L at room temperature, then adding solid tazobactam diphenyl ester 4 (48 g, 102.89 mmol) and 5% Pd/C (4.8 g), uniformly stirring, then introducing hydrogen into the high-pressure autoclave to 0.1 MPa, then discharging gas to 0.02 MPa (hydrogen replacement for 3 times), finally introducing hydrogen to 0.6 MPa, then heating the system to 60 ℃, stirring for about 6 hours, after the reaction of the raw materials is finished, cooling the system to room temperature, slowly discharging gas from the high-pressure autoclave, replacing the gas with nitrogen once, finally discharging the gas into the high-pressure autoclave without pressure, filtering the system, leaching a filter cake with 3v 2 methanol, combining filtrates, concentrating the filtrate until no fraction is obtained to obtain a crude tazobactam product with the HPLC yield of 99.8%, and separating the yield of 85%.
Nuclear magnetic hydrogen spectrum data of tazobactam: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 1.1 Hz, 1H), 7.79 (d, J = 1.1 Hz, 1H), 5.21 (m, 1H), 4.96 (d, J = 15.5 Hz, 2H), 4.79 (s, 1H), 3.31-3.72 (m, 2H), 1.34 (s, 3H).
Example 2
The difference between example 2 and example 1 is that in the second step, 8.0 eq of 1,2, 3-triazole is added to obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further tazobactam.
Example 3
The difference between the example 3 and the example 1 is that in the second step of reaction, the addition amount of 1,2, 3-triazole is 15eq, so that 2 beta-triazole methyl penicillanic acid diphenylmethyl ester 3 is finally obtained, and further, tazobactam is obtained.
Example 4
Example 4 is different from example 1 in that in the second step, the amount of 1,2, 3-triazole is 20 eq, and 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3 and further tazobactam are obtained.
Example 5
Example 5 is different from example 1 in that in the second step, the amount of 1,2, 3-triazole is 2 eq to obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 6
Example 6 is different from example 1 in that 1.5 eq of 1,2, 3-triazole is added in the second reaction step to finally obtain 2 beta-triazole methyl penicillanic acid diphenylmethyl ester 3 and further obtain tazobactam.
Example 7
Example 7 is different from example 1 in that 50wt% hydrogen peroxide is used instead of ceric amine nitrate to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 8
Example 8 is different from example 1 in that cumene hydroperoxide is used instead of ceric amine nitrate in the second reaction step to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam is obtained.
Example 9
Example 9 is different from example 1 in that cerium nitrate amine is added in an amount of 0.5eq in the second reaction step to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 10
Example 10 is different from example 1 in that cerium nitrate amine is added in an amount of 10eq in the second reaction step to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 11
Example 11 is different from example 1 in that cerium nitrate amine is added in an amount of 0.4eq in the second reaction step to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 12
Example 12 is different from example 1 in that cerium nitrate amine is added in an amount of 15eq in the second reaction step to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 13
Example 13 differs from example 1 in that in the second reaction step, 1, 4-dioxane is used instead of acetone to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 14
Example 14 differs from example 1 in that in the second reaction step, isopropanol is used instead of acetone to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 15
Example 15 differs from example 1 in that in the second reaction step, disulfide ring-opened compound 2 (about 90 g) was dissolved in acetone (900 mL) to finally obtain 2 β -tolyltriazole penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 16
Example 16 differs from example 1 in that, in the second reaction step, disulfide ring-opened compound 2 (about 90 g) was dissolved in acetone (1350 mL) to finally obtain 2 β -tolyltriazole penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 17
Example 17 differs from example 1 in that in the second reaction step, disulfide ring-opened compound 2 (about 90 g) was dissolved in acetone (45 mL) to finally obtain 2 β -tolyltriazole penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 18
Example 18 differs from example 1 in that in the second reaction step, disulfide ring-opened compound 2 (about 90 g) was dissolved in acetone (4500 mL) to finally obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam.
Example 19
The difference between the embodiment 19 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 18 hours at a temperature of 25-28 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 20
The difference between the embodiment 20 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 18 hours at a temperature of 35-40 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 21
The difference between the embodiment 21 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 18 hours at a temperature of 20-23 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 22
The difference between the embodiment 22 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 18 hours at 47-50 ℃ under heat preservation, and finally 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3 is obtained, and further tazobactam is obtained.
Example 23
The difference between the embodiment 23 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 18 hours at 55-58 ℃ under heat preservation, and finally 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3 is obtained, and further tazobactam is obtained.
Example 24
The difference between the embodiment 24 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 15 hours at a temperature of 28-33 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 25
The difference between the embodiment 25 and the embodiment 1 is that in the second step of reaction, the system is stirred for about 24 hours at a temperature of 28-33 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 26
The difference between the example 26 and the example 1 is that in the second step of reaction, the system is stirred for about 2 hours at a temperature of 28-33 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 27
The difference between the example 27 and the example 1 is that in the second step of reaction, the system is stirred for about 48 hours at a temperature of 28-33 ℃ to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 28
Example 28 is different from example 1 in that in the second step, 0.2 eq acetic acid is added as additive to the system to obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further tazobactam.
Example 29
Example 29 is different from example 1 in that in the second step, 0.5eq acetic acid is added as additive to the system to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 30
Example 30 is different from example 1 in that in the second step, 0.8 eq acetic acid is added as additive to obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3 and tazobactam.
Example 31
Example 31 is different from example 1 in that in the second step, 0.05 eq of acetic acid is added as an additive to the system to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 32
Example 32 is different from example 1 in that in the second step, 1eq acetic acid is added as additive to the system to finally obtain 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further obtain tazobactam.
Example 33
Example 33 is different from example 1 in that in the second step, 0.2 eq triethylamine is added as an additive to obtain 2 β -tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, and further, tazobactam is obtained.
Example 34
Example 34 differs from example 1 in that the charge amount of sodium tungstate in the third reaction step is 0.2 equivalent, and tazobactam diphenylmethyl ester 4 and further tazobactam are finally obtained.
Example 35
Example 35 differs from example 1 in that in the third reaction step, the amount of sodium tungstate charged is 0.01 equivalent, and tazobactam diphenylmethyl ester 4 and further tazobactam are finally obtained.
Example 36
Example 36 is different from example 1 in that in the third reaction step, the charge amount of 35% hydrogen peroxide is 8 equivalents, and tazobactam diphenylmethyl ester 4 and further tazobactam are finally obtained.
Example 37
Example 37 is different from example 1 in that, in the third reaction step, the charge amount of 35% hydrogen peroxide is 2 equivalents, and tazobactam diphenylmethyl ester 4 and further tazobactam are finally obtained.
Example 38
Example 38 is different from example 1 in that, in the third reaction step, the charge amount of 35% hydrogen peroxide is 10 equivalents, and tazobactam diphenylmethyl ester 4 and further tazobactam are finally obtained.
Example 39
Example 39 differs from example 1 in that in the third step, 0.5 equivalent of trifluoroacetic acid and 0.5 equivalent of p-toluenesulfonic acid are used instead of sulfuric acid and phosphoric acid additive, the solvent is tetrahydrofuran, the temperature of the oxidation reaction is 40 ℃, and the reaction is carried out for 3h to finally obtain tazobactam diphenylmethyl ester 4 and further obtain tazobactam.
Example 40
Example 40 is different from example 1 in that, in the third step of reaction, 0.05 equivalent of trifluoroacetic acid and 0.05 equivalent of p-toluenesulfonic acid are adopted to replace sulfuric acid and phosphoric acid additive, the solvent is dichloroethane, the temperature of oxidation reaction is 20 ℃, the reaction time is 20 hours, tazobactam diphenylmethyl ester 4 is finally obtained, and furthermore, tazobactam is obtained.
EXAMPLE 41
Example 41 is different from example 1 in that in the fourth step of reaction, Rh/C is used as a catalyst, acetonitrile is used as a solvent, the temperature of deprotection reaction is 75 ℃, and the reaction time is 20h, so that tazobactam is finally obtained.
Example 42
Example 42 differs from example 1 in that in the fourth reaction step Pd/Al is used2O3The catalyst is used, the solvent is 1, 4-dioxane, the deprotection reaction temperature is 90 ℃, the reaction time is 24 hours, and finally the tazobactam is obtained.
Example 43
Example 43 differs from example 1 in that in the fourth reaction step Pd/Al is used2O3Is used as a catalyst, a solvent is trichloromethane, the deprotection reaction temperature is 20 ℃, the reaction time is 1h, and finally tazobactam is obtained.
Example of the amplification reaction:
the embodiment of the amplification reaction is different from the embodiment 1 in that the disulfide ring-opening compound 2 is amplified to 5kg, the dosage of the other raw materials is also amplified according to the corresponding proportion, and the reaction is carried out under the reaction conditions of the embodiment 1, so that tazobactam is finally obtained, the yield is 53.6%, the HPLC purity of the product is 99.8%, and the nuclear magnetic content of the product is 99%.
Comparative example 1
In a first step, the disulfide ring-opened compound 2 was prepared by the following route:
adding toluene (975 mL) into a four-mouth bottle provided with a water separator at room temperature, then sequentially adding 2-mercaptobenzothiazole (28.92 g, 172.90 mmol and 1.02 eq) and penicillanic sulfoxide acid diphenylmethyl ester 1(65 g, 169.51 mmol and 1.0 eq) into a system, then heating the system to 120 ℃, refluxing and dividing water for 2 hours, after the reaction of the raw materials is finished, rapidly cooling the system to room temperature, controlling the temperature to be 30-40 ℃, concentrating the product at High Performance Liquid Chromatography (HPLC) purity and the external standard yield of the system to 95%, and directly using the product for the next reaction after controlling the temperature to be 30-40 ℃ until no fraction is produced.
Secondly, preparing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester 3 by the following route:
at room temperature, adding solvent DCM (858mL, 10v) into the crude product of the first step, stirring and dissolving, and clarifying the system; then anhydrous copper chloride (23.82 g, 1.1 eq) was added and the system was cloudy; controlling the temperature of the system to be 25 ℃, and continuously stirring for 5-6 hours, wherein the system gradually becomes dark green and turbid after the reaction is finished; filtering the system, fully soaking the filter cake in DCM (3 v × 2) for 15min, performing suction filtration, combining organic phases, sequentially washing the organic phases with 5% sodium bicarbonate water solution and saturated saline solution respectively once, and performing reduced pressure concentration on the organic phases at 25 ℃ to obtain a reddish brown turbid oily substance; then acetonitrile (772 mL, 9v) is added into the oily substance, and the oily substance is stirred and dissolved, so that the system is clear; purified water (257.4 mL, 3v), WA30 resin (60.06g, 0.7g/g) and triazole (278 g, 25 eq) are sequentially added into the system, and then the system is heated to 30 ℃ and stirred for 2-4 h to complete the reaction. After the reaction, the system was concentrated at 30 ℃, the aqueous phase was extracted twice with 8v and 5v dichloromethane respectively, and the organic phases were combined; washing the organic phase with purified water (2 v 5), concentrating at 30 ℃ to obtain wine red oily liquid, and performing crystallization by using methyl tert-butyl ether to obtain a target product 2 beta-tolyltriazole methyl penicillanic acid diphenylmethyl ester 3, wherein the yield of the two-step separation is 60%.
Step three, preparing tazobactam diphenylmethyl ester 4 by the following route:
at room temperature, adding 2 beta-triazole methyl penicillanic acid diphenylmethyl ester (42 g), dichloromethane (504 mL, 12 v), glacial acetic acid (84 mL, 2 v) and purified water (168 mL, 4 v) into a four-mouth bottle, and cooling the system to 0-10 ℃. And (3) controlling the temperature, adding potassium permanganate (38.2 g, 2.5 eq) in batches, stirring and reacting for 5-7 h at 20-25 ℃ after the addition is finished, and finishing the reaction. Controlling the temperature to be 0-10 ℃, dropwise adding 50% hydrogen peroxide into the system until the reaction solution fades to be colorless, filtering the system, drying the filtrate, adding ethyl acetate (84 v, 2 v), cooling to 0-5 ℃, stirring for 2-3 h, and filtering to obtain a target product tazobactam diphenylmethyl ester 4, wherein the separation yield is 88%.
Fourthly, preparing tazobactam by the following route:
at room temperature, adding raw materials (39.68 g) and m-methylphenol (317 mL, 8 v) into a four-mouth bottle, heating the system to 50-60 ℃, keeping the temperature and stirring for 2-4 h at the temperature, and then finishing the reaction. Quickly reducing the temperature of the system to below 15 ℃, adding 7-8% of sodium bicarbonate water solution (119 mL, 3v), and continuously stirring for 30-45 min; then, ethyl acetate (397 mL, 10V) is added into the system and stirred for 5-15 min. The method comprises the steps of standing at 0-10 ℃, separating liquid, keeping the temperature at 0-10 ℃, extracting an organic phase once by using a 7-8% sodium bicarbonate aqueous solution (0.3v), combining aqueous phases, cooling the aqueous phase to 0-5 ℃, slowly dropwise adding 6M hydrochloric acid to adjust the pH to be 1-2, separating out white solids, stirring at 0 ℃ for 1 hour, filtering, washing a filter cake with water, drying the filter cake with nitrogen at room temperature, wherein the HPLC purity of the solid is 98%, and the separation yield is 80%.
The isolated yields of benzhydryl 2 β -tolylpenicillanic acid 3 (identified as intermediate 3) and the total yield of tazobactam obtained in examples 1 to 33 were calculated, respectively, and the results are shown in table 1.
TABLE 1
The isolated yields of tazobactam benzhydryl ester 4 (identified as intermediate 4) and the total yield of tazobactam obtained in examples 34 and 40, respectively, were calculated and the results are shown in table 2.
TABLE 2
The total yield of tazobactam obtained in examples 41 and 43 was calculated, respectively, and the results are shown in Table 3.
TABLE 3
Therefore, the reaction of tazobactam can be amplified for production, and has great industrial application value.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
under the action of a first oxidant, 1,2, 3-triazole is used for directly closing a disulfide ring-opening compound, so that a chloride intermediate with poor stability is avoided, and the high-efficiency and high-selectivity synthesis of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester from the disulfide ring-opening compound directly to a key intermediate is successfully realized. Compared with the current route for industrially producing 2 beta-tolylpenicillanic acid diphenylmethyl ester, the strategy not only shortens the reaction step, but also greatly improves the selectivity of the target product 2 beta-tolylpenicillanic acid diphenylmethyl ester, thereby obviously improving the reaction yield of the 2 beta-tolylpenicillanic acid diphenylmethyl ester, and further, the 2 beta-tolylpenicillanic acid diphenylmethyl ester is used as a key intermediate for synthesizing tazobactam, so that the yield of tazobactam is improved, and the cost is reduced.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A preparation method of 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is characterized by comprising the following steps:
reacting reaction raw materials comprising a disulfide ring-opening compound, 1,2, 3-triazole and a first oxidant in a first solvent to obtain a product system comprising 2 beta-triazole methyl penicillanic acid diphenylmethyl ester,
wherein the structural formula of the disulfide ring-opening compound is shown in the specification
The structural formula of the 2 beta-triazole methyl penicillanic acid diphenylmethyl ester is shown in the specification
，
The first oxidant is one or more of ammonium ceric nitrate, 5-50 wt% of hydrogen peroxide, tert-butyl hydroperoxide, carbamide peroxide and cumene hydroperoxide,
the reaction temperature is 20-50 ℃, and the reaction time is 2-48 h.
2. The preparation method of claim, wherein the molar ratio of the 1,2, 3-triazole to the first oxidant is 1-20: 1.
3. The preparation method according to claim 1, wherein the molar ratio of the 1,2, 3-triazole to the disulfur ring-opening compound is 2-20: 1.
4. the method according to claim 1, wherein the mass ratio of the volume of the first solvent to the disulfur ring-opening compound is 5 to 50 mL:1g, and the first solvent is selected from any one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, trichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol and hexafluoroisopropanol.
5. The production method according to claim 1, wherein a first additive that promotes the reaction is added, and the molar ratio of the first additive to the disulfur ring-opening compound is 0.05 to 1:1, the first additive is selected from one or more of acetic acid, hydrochloric acid, phosphoric acid, hypoboric acid, phenylboronic acid, hexafluoroisopropanol, triethylamine, diisopropylethylamine, triphenylphosphine, 1 '-binaphthyl-2, 2' -diphenylphosphine, aluminum oxide and silver nitrate.
6. A method for preparing a tazobactam intermediate, wherein the tazobactam intermediate has a structural formula:
the preparation method is characterized by comprising the following steps:
step S1, preparing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester by the preparation method of any one of claims 1 to 5;
step S2, carrying out oxidation reaction on the 2 beta-triazole methyl penicillanic acid diphenylmethyl ester under the action of a second oxidant and a first catalyst to obtain a tazobactam intermediate,
the second oxidant is selected from one or more of potassium permanganate, 5-50 wt% of hydrogen peroxide, tert-butyl hydroperoxide, ammonium persulfate, potassium peroxymonosulfonate, carbamide peroxide and cumene hydroperoxide, the feeding amount of the second oxidant is 2-10 equivalent,
the temperature of the oxidation reaction is 20-60 ℃, and the time of the oxidation reaction is 1-24 h.
7. The preparation method according to claim 6, wherein the first catalyst is selected from one or more of sodium tungstate, tungstic acid and rhenium trioxide, and the dosage of the first catalyst is 0.01-0.2 equivalent.
8. The method according to claim 6, wherein a second additive for promoting the oxidation reaction is added in an amount of 0.1 to 1 equivalent, and the second additive is one or more selected from phosphoric acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
9. The preparation method according to claim 6, wherein the oxidation reaction is carried out in a second solvent, the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol and hexafluoroisopropanol, and the mass ratio of the volume of the second solvent to the 2 β -tolylpenicillanic acid diphenylmethyl ester is 5-20 mL:1 g.
10. A preparation method of tazobactam, which is characterized by comprising the following steps:
step S1 of preparing a tazobactam intermediate using the preparation method of any one of claims 6 to 9;
step S2, performing deprotection on the tazobactam intermediate to prepare tazobactam.
11. The method for preparing a composite material according to claim 10, wherein the step S2 includes:
and carrying out deprotection reaction on the tazobactam intermediate under the action of hydrogen and a second catalyst to obtain the tazobactam.
12. The preparation method of claim 11, wherein the second catalyst is fed in an amount of 5-20 wt% of the tazobactam intermediate, and the second catalyst is selected from Pd/C, Rh/C, Pd/Al2O3Any one or more of them.
13. The method according to claim 10, wherein the temperature of the deprotection reaction is 20 to 90 ℃ and the time of the deprotection reaction is 1 to 24 hours.
14. The preparation method according to claim 10, wherein the deprotection reaction is carried out in a third solvent selected from any one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, isopropanol, and hexafluoroisopropanol, and the mass ratio of the volume of the third solvent to the tazobactam intermediate is 5 to 20mL:1 g.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58220653A (en) * | 1982-06-17 | 1983-12-22 | Ajinomoto General Food Kk | Preparation of coffee extract |
| CN102304139A (en) * | 2011-07-12 | 2012-01-04 | 景德镇市富祥药业有限公司 | Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide |
| CN104031065A (en) * | 2014-04-01 | 2014-09-10 | 江西华邦药业有限公司 | Preparation method for tazobactam |
| CN107033161A (en) * | 2017-05-04 | 2017-08-11 | 石家庄万业化工科技有限公司 | A kind of synthetic method of tazobactam |
| CN108061550A (en) * | 2017-11-03 | 2018-05-22 | 中航通飞研究院有限公司 | A kind of engine parameter acquisition and sensor total system |
| CN109053767A (en) * | 2018-08-30 | 2018-12-21 | 凯莱英医药集团（天津）股份有限公司 | The synthetic method of Tazobactam Sodium benzhydryl ester |
| CN109305977A (en) * | 2018-11-28 | 2019-02-05 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of Tazobactam Sodium |
| CN109503628A (en) * | 2018-11-28 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of Tazobactam Sodium chiral isomer |
| CN111777624A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester |
| CN111777623A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester and tazobactam acid |
| CN113073348A (en) * | 2021-03-29 | 2021-07-06 | 吉林凯莱英制药有限公司 | Method for electrochemically synthesizing tazobactam key intermediate |
-
2021
- 2021-10-25 CN CN202111237441.XA patent/CN113666946B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58220653A (en) * | 1982-06-17 | 1983-12-22 | Ajinomoto General Food Kk | Preparation of coffee extract |
| CN102304139A (en) * | 2011-07-12 | 2012-01-04 | 景德镇市富祥药业有限公司 | Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide |
| CN104031065A (en) * | 2014-04-01 | 2014-09-10 | 江西华邦药业有限公司 | Preparation method for tazobactam |
| CN107033161A (en) * | 2017-05-04 | 2017-08-11 | 石家庄万业化工科技有限公司 | A kind of synthetic method of tazobactam |
| CN108061550A (en) * | 2017-11-03 | 2018-05-22 | 中航通飞研究院有限公司 | A kind of engine parameter acquisition and sensor total system |
| CN109053767A (en) * | 2018-08-30 | 2018-12-21 | 凯莱英医药集团（天津）股份有限公司 | The synthetic method of Tazobactam Sodium benzhydryl ester |
| CN109305977A (en) * | 2018-11-28 | 2019-02-05 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of Tazobactam Sodium |
| CN109503628A (en) * | 2018-11-28 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of Tazobactam Sodium chiral isomer |
| CN111777624A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester |
| CN111777623A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester and tazobactam acid |
| CN113073348A (en) * | 2021-03-29 | 2021-07-06 | 吉林凯莱英制药有限公司 | Method for electrochemically synthesizing tazobactam key intermediate |
Non-Patent Citations (2)
| Title |
|---|
| β-内酰胺酶抑制剂他唑巴坦的合成;仲兆金等;《中国新药杂志》(第01期);全文 * |
| 新型β-内酰胺酶抑制剂他唑巴坦的合成;刘秀兰等;《太原理工大学学报》;20021120(第06期);全文 * |
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