CN113073348B - Method for electrochemically synthesizing tazobactam key intermediate - Google Patents
Method for electrochemically synthesizing tazobactam key intermediate Download PDFInfo
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Abstract
The invention provides a method for electrochemically synthesizing a tazobactam key intermediate. The method comprises the following steps: taking the disulfide ring-opening compound A and the 1,2, 3-triazole B as reaction substrates, mixing the reaction substrates, electrolyte and reaction solvent, and then carrying out electrochemical anodic oxidation to obtain a tazobactam key intermediate C. The invention effectively solves the problems of low selectivity, low reaction efficiency or poor economy and the like when 2 beta-triazole methyl penicillic acid diphenylmethyl ester is synthesized in the prior art.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for electrochemically synthesizing a tazobactam key intermediate.
Background
In 1940, penicillin was applied to clinical therapeutic research, and this β -lactam antibiotic has developed into cephalosporin with excellent anti-infective effect, and it exerts therapeutic effect by inhibiting penicillin binding protein. Through researching the structure-activity relationship of the penicillanic sulfone derivative, the beta-lactam antibiotics with stronger activity and wider enzyme resisting spectrum can be obtained by modifying the 6-position or the 2 beta-methyl position. Among them, Tazobactam (Tazobactam) is the most effective. Tazobactam can generate effective synergistic action with various beta-lactam antibiotics, so that the antibacterial activity is increased and the antibacterial spectrum is expanded. The compound tazobactam preparation has strong curative effect on infection of abdominal cavity, respiratory tract, urinary tract, skin tissue, etc. and obvious curative effect on paediatrics, burns, hematopathy, etc.
Tazobactam is successfully developed by the Japan Roc drug company for the first time in the eighties of the last century, and the synthetic route and the process of tazobactam are continuously improved along with the continuous improvement of the organic synthesis level. At present, the synthesis method mainly comprises three synthetic routes according to the difference of raw materials adopted in the synthesis, and derivatives such as penicillin G potassium salt, sulbactam, 6-aminopenicillanic acid and the like are respectively used as starting materials. Taking the example of the penicillanic acid diphenylmethyl ester, the final product is obtained after cracking ring opening, chloromethylation, triazole oxidation and deprotection. However, the method has the problems of long reaction steps, low conversion rate, poor economic benefit and the like.
In the above synthetic route, diphenyl methyl 2 beta-triazolyl methyl penicillate (IV) is one of the key intermediates, and the low conversion rate of the triazolation reaction (step 3) is also a key problem of low yield of the whole synthetic route. Foreign patents (EP1813619a1, US7714125B2, US20150246931a1) and chinese patents (CN 107033161a, CN 105085544a, CN 107033161a) all report that disulfide ring-opened product (II) is used as raw material, and undergoes cyclization and halogenation to obtain intermediate III, and then 2 β -triazole methyl penicillanic acid diphenylmethyl ester (IV) is obtained under the action of cationic resin (see below). However, this synthetic route also has problems of long reaction steps, difficulty in selectivity control, complicated post-treatment, and the like. In addition, a few reports (Synthesis 2005,3, 442-. However, in this reaction, triazole needs to react with an equivalent amount of silver salt to obtain 1,2, 3-triazole silver salt (J. chem. Soc., Dalton trans.,1998, 1653-1659), which is economically inefficient and disadvantageous for scale-up due to the expensive and difficult recovery of silver salt.
In a word, when the tazobactam key intermediate, namely 2 beta-triazole methyl penicillanic acid diphenylmethyl ester (IV) is synthesized at present, most reports aiming at the existing disulfur ring-opening product as a raw material and constructing 2 beta-triazole penicillanic acid diphenylmethyl ester (IV) need to firstly carry out halogenation ring closing and then carry out nucleophilic substitution on 1,2, 3-triazole to obtain a product. In the halogenation reaction, the isomers of the five-membered ring and the six-membered ring have poor selectivity; in the substitution reaction, a cationic resin needs to be added, and the conversion rate is low. In the reaction of using 1,2, 3-triazole silver salt to construct 2 beta-triazole penicillanic acid diphenylmethyl ester (IV) in one step, 1,2, 3-triazole needs to be pre-functionalized, and the use of equivalent silver salt causes expensive raw materials and low economic benefit. Therefore, it is necessary to provide a process for preparing diphenylmethyl 2 β -triazolylmethylpenicilate with high selectivity, fast reaction efficiency and high economy.
Disclosure of Invention
The invention mainly aims to provide a method for electrochemically synthesizing a tazobactam key intermediate, which aims to solve the problems of low selectivity, low reaction efficiency, poor economy and the like in the process of synthesizing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester 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 electrochemically synthesizing tazobactam key intermediates, comprising the steps of: taking the disulfide ring-opening compound A and the 1,2, 3-triazole B as reaction substrates, mixing the reaction substrates with electrolyte and reaction solvent, and then carrying out electrochemical anodic oxidation to obtain a tazobactam key intermediate C; the reaction route of the electrochemical anodic oxidation process is as follows:
further, in the electrochemical anodic oxidation process, the adopted anode is selected from a carbon rod electrode, a carbon felt electrode, a carbon paper electrode, a carbon cloth electrode, a platinum electrode, an RVC electrode or a BDD electrode; the cathode is selected from nickel, platinum, iron, graphite, gold or silver electrode, and the cathode is sheet, net, rod or wire electrode.
Further, the electrolyte comprises an iodine-containing electrolyte, preferably one or more of tetrabutylammonium iodide, potassium iodide, sodium iodide, zinc iodide, lithium iodide, cuprous iodide and iodine elementary substance; preferably, when the electrolyte only comprises the iodine-containing electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1.
Further, the electrolyte also comprises an additional electrolyte, and the additional electrolyte is selected from one or more of inorganic salt, quaternary ammonium salt and perchlorate; preferably, when the general formula of the electrolyte comprises an iodine-containing electrolyte and an additional electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 0.18-0.24: 1, and the molar ratio of the additional electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1.
Further, the inorganic salt is selected from one or more of sodium chloride, sodium sulfate, sodium acetate, lithium chloride and potassium sulfate; the quaternary ammonium salt is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium chloride and tetrabutylammonium bromide; the perchlorate is selected from lithium perchlorate and/or sodium perchlorate.
Further, the reaction solvent comprises a first solvent and a second solvent, wherein the first 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, hexafluoroisopropanol; the second solvent is one or more selected from formic acid, acetic acid, propionic acid, butyric acid and valeric acid.
Further, the volume ratio of the first solvent to the second solvent is 1-20: 1, preferably 8-10: 1.
Furthermore, in the reaction substrate, the molar ratio of the disulfide ring-opening compound A to the 1,2, 3-triazole B is 1: 2-20, and preferably 1: 7-10.
Further, the treatment temperature in the electrochemical anodic oxidation process is 24-28 ℃.
Further, the electrochemical anodic oxidation process is carried out in a constant current mode, and the current density is 4-30 mA/cm2Preferably 10 to 15mA/cm2(ii) a Preferably, the reaction electric quantity in the electrochemical anodic oxidation process is 2-8F, and more preferably 5-5.5F.
The invention takes the disulfide ring-opening compound A and the 1,2, 3-triazole B as reaction substrates, and utilizes electrochemical anodic oxidation to realize the high-efficiency and high-selectivity synthesis of the tazobactam key intermediate, namely 2 beta-triazole methyl penicillanic acid diphenylmethyl ester. Compared with the existing reports, the method has the advantages of few reaction steps, no need of pre-functionalization, high selectivity, high reaction efficiency and the like. The electrochemical method can well avoid the steps of cyclizing halogenation and 1,2, 3-triazole pre-functionalization, and 2 beta-triazole methyl penicillanic acid diphenylmethyl ester C is synthesized in one step by directly taking the disulfide ring-opening compound A and the 1,2, 3-triazole B as substrates, so that the step economy is improved, and the post-treatment steps and the generated three wastes are reduced.
In a word, the method effectively solves the problems of low selectivity, low reaction efficiency or poor economy and the like when the 2 beta-triazole methyl penicillate benzhydryl ester is synthesized in the prior art.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
figure 1 shows the nuclear magnetic spectrum of the product of the example 1 according to the invention.
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 below with reference to the embodiments with reference to the attached drawings.
As described in the background section, the prior art has the problems of low selectivity, low reaction efficiency or poor economy when synthesizing 2 beta-triazole methyl penicillanic acid diphenylmethyl ester. In order to solve the above problems, the present invention provides a method for electrochemically synthesizing a tazobactam key intermediate, which is characterized by comprising the following steps:
taking the disulfide ring-opening compound A and the 1,2, 3-triazole B as reaction substrates, mixing the reaction substrates with electrolyte and reaction solvent, and then carrying out electrochemical anodic oxidation to obtain a tazobactam key intermediate C; the reaction route of the electrochemical anodic oxidation process is as follows:
the invention takes the disulfide ring-opening compound A and the 1,2, 3-triazole B as reaction substrates, and utilizes electrochemical anodic oxidation to realize the high-efficiency and high-selectivity synthesis of the tazobactam key intermediate, namely 2 beta-triazole methyl penicillanic acid diphenylmethyl ester. Compared with the existing reports, the method has the advantages of few reaction steps, no need of pre-functionalization, high selectivity, high reaction efficiency and the like. The electrochemical method can well avoid the steps of cyclizing halogenation and 1,2, 3-triazole pre-functionalization, and 2 beta-triazole methyl penicillanic acid diphenylmethyl ester C is synthesized in one step by directly taking the disulfide ring-opening compound A and the 1,2, 3-triazole B as substrates, so that the step economy is improved, and the post-treatment steps and the generated three wastes are reduced.
In a word, the invention effectively solves the problems of low selectivity, low reaction efficiency or poor economy and the like when 2 beta-triazole methyl penicillate diphenylmethyl is synthesized in the prior art.
In a preferred embodiment, the anode used in the electrochemical anodization process includes, but is not limited to, a carbon rod electrode, a carbon felt electrode, a carbon paper electrode, a carbon cloth electrode, a platinum electrode, an RVC electrode, or a BDD electrode; the cathode used includes, but is not limited to, nickel, platinum, iron, graphite, gold or silver electrode, and the cathode is a sheet, mesh, rod or wire electrode.
In a preferred embodiment, the electrolyte comprises iodine-containing electrolyte, preferably one or more of tetrabutylammonium iodide, potassium iodide, sodium iodide, zinc iodide, lithium iodide, cuprous iodide and iodine simple substance. The iodine-containing substances are used as electron transfer media, so that the iodine-containing substances have the functions of electrolytes and phase transfer catalysts on the one hand, the conductivity of a reaction system is improved, and the reaction efficiency is improved. It should be noted that, precisely because the present invention adopts the electrochemical anode oxidation method, the above-mentioned several kinds of iodides can be oxidized into high-valence iodine intermediates, and then the reaction conversion is promoted. The strategy avoids expensive high-price iodine reagent, the reagent is green, the condition is mild, and compared with other electrolytes such as quaternary ammonium salt, perchlorate and ionic liquid, the system is more uniform, and the method is favorable for electron transfer and mass transfer. Preferably, when the electrolyte only comprises the iodine-containing electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1, and more preferably 2:1, and the iodine-containing electrolyte acts as an electron transfer medium and also as a catalyst.
Of course, when a catalytic amount of iodide is used as a catalyst, the electrolyte further includes an additional electrolyte selected from one or more of inorganic salts, quaternary ammonium salts and perchlorate salts in a preferred embodiment for the purpose of further improving the conductivity of the system. Preferably, the inorganic salt includes, but is not limited to, one or more of sodium chloride, sodium sulfate, sodium acetate, lithium chloride, potassium sulfate; the quaternary ammonium salt comprises one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium chloride and tetrabutylammonium bromide; perchlorates include, but are not limited to, lithium perchlorate and/or sodium perchlorate. In addition, the iodine compound in catalytic amount is used as an electron transfer medium, and quaternary ammonium salt is added as electrolyte, so that the substrate can be oxidized by high-valence iodine and then returns to a low-valence state again, thereby realizing recycling, and the iodine compound can be added in catalytic amount. Preferably, when the general electrolyte formula comprises the iodine-containing electrolyte and the additional electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 0.18-0.24: 1, more preferably 0.2:1, and the molar ratio of the additional electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1, more preferably 2: 1.
In order to improve the solubility of the reaction substrate and the electrolyte, etc., and to make the reaction more stable, in a preferred embodiment, the reaction solvent includes a first solvent and a second solvent, wherein the first 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, dimethylsulfoxide, methanol, ethanol, isopropanol, hexafluoroisopropanol; the second solvent is selected from one or more of organic weak acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, etc. More preferably, the volume ratio of the first solvent to the second solvent is 1-20: 1, preferably 8-10: 1, and most preferably 9: 1.
In a preferred embodiment, the molar ratio of the disulfide ring-opening compound a to the 1,2, 3-triazole B in the reaction substrate is 1: 2-20, preferably 1: 7-10, and most preferably 8: 1. The dosage relationship of the two reaction substrates is controlled in the range, which is favorable for further improving the reaction efficiency and the reaction selectivity.
In the actual treatment process, the reaction selectivity and the conversion rate can be further improved by adjusting the process conditions in the electrochemical anodic oxidation process, and in a preferred embodiment, the treatment temperature in the electrochemical anodic oxidation process is 24-28 ℃; preferably, the electrochemical anodic oxidation process is carried out in a constant current mode, and the current density is 4-30 mA/cm2More preferably 10 to 15mA/cm2. In addition, for small quantities (e.g. for<0.5mmol) in the reaction, the dead area of the used electrode is too small, and a reaction constant current mode can be set. Preferably, the reaction electric quantity in the electrochemical anodic oxidation process is 2-8F, and more preferably 5-5.5F. Here, 1F represents the amount of electricity required to transfer 1mol of electrons. Under the process conditions, high-selectivity conversion can be realized in a shorter time, the step of pre-functionalization is avoided, the production efficiency is greatly improved, and the treatment difficulty of three wastes is reduced.
The electrochemical anodic oxidation process can be carried out in an air atmosphere or in a pure oxygen system.
In addition, based on the scheme, the total yield of the 2 beta-triazole methyl penicillate diphenylmethyl ester can be improved, the separation yield can be improved to 76%, and the product purity is 95%.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1: preparation of 2 beta-Triazolylmethylpenicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2(the current density at this time was 4mA/cm2). The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction is finished, a reaction solution is sampled and sent to an HPLC external standard, the yield is 76.8%, and white solid is obtained through column chromatography separation, and the yield is 76.2%.
The nuclear magnetic spectrum of the white solid is shown in figure 1, and the hydrogen spectrum data is as follows:1H NMR(400MHz,Chloroform-d)δ7.78–7.72(m,2H),7.40–7.27(m,10H),6.90(s,1H),5.41(dd,J＝4.1,1.8Hz,1H),4.88(s,1H),4.66–4.53(m,2H),3.72–3.61(m,1H),3.17(dd,J＝16.1,1.8Hz,1H),1.21(s,3H)。
example 2: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C by using carbon felt as anode
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the materials are added, the equipment is provided with a carbon felt (1 multiplied by 7 cm)2) And platinum sheet (1X 7X 0.3 cm)3) As cathode and anode, the electrode immersion area is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 71.0%.
Example 3: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C by using iron sheet as cathode
At room temperature, magnetons were added to a non-diaphragm cell (8mL), followed byThe disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), and tetrabutylammonium iodide (185mg,0.5mmol,2eq) were added to the vessel. Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the equipment is equipped with graphite flakes (1X 7 cm)2) And iron sheet (1X 7X 0.2 cm)3) As cathode and anode, the electrode immersion area is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 49.2%.
Example 4: 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C prepared from 2eq,1,2, 3-triazole
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (34.5mg, 0.5mmol,2eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the equipment is equipped with graphite flakes (1X 7 cm)2) And platinum sheet (1X 7X 0.3 cm)3) As cathode and anode, the immersed area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and sent to HPLC external standard with a yield of 15.8%.
Example 5: preparation of 2 beta-triazolylmethylpenicillanic acid diphenylmethyl ester C from 20eq 1,2, 3-triazole
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole (345mg, 5mmol,20 eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the equipment is equipped with graphite flakes (1X 7 cm)2) And platinum sheet (1X 7X 0.3 cm)3) As cathode and anode, the electrode immersion area is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 75.1%.
Example 6: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C by catalytic amount of tetrabutylammonium iodide
Magnetons were added to a non-diaphragm electrolytic cell (8mL) at room temperature, followed by disulfide ring-opener a (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (18.5mg,0.05mmol,20 mol%), tetrabutylammonium tetrafluoroborate (164.6mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 6.5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 68.7%.
Example 7: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C by adding inorganic salt electrolyte
Magnetons were added to a non-diaphragm electrolytic cell (8mL) at room temperature, followed by disulfide ring-opener a (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (18.5mg,0.05mmol,20 mol%), sodium sulfate (71mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 6.5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and sent to HPLC external standard with a yield of 48.9%.
Example 8: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C with participation of potassium iodide
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by addition of disulfide ring-opener a (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), and potassium iodide (83mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. Stirring the reaction solution for 10min, mixing thoroughly, and regulating direct currentSource to galvanostatic mode, 8mA electrolyzes 5F to complete conversion of the feedstock. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 53.0%.
Example 9: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C with participation of lithium iodide
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by disulfide ring-opener a (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), and lithium iodide (56.9mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and sent to HPLC external standard with a yield of 48.6%.
Example 10: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C by using methanol as solvent
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Methanol (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 28.4%.
Example 11: mixed solvent ratio 1: 1 preparation of 2 beta-Triazolylmethylpenicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (2.5mL) and acetic acid (2.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction is finished, the reaction liquid is sampled and sent to an HPLC external standard, the yield is 76.8 percent, and the white solid is obtained by column chromatography separation, and the yield is 62.3 percent.
Example 12: the mixed solvent ratio is 20:1 preparation of 2 beta-Triazolylmethylpenicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (5mL) and acetic acid (0.25mL, 4eq) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, and 8mA is electrolyzed for 5F until the raw materials are completely converted. After the reaction is finished, the reaction liquid is sampled and sent to an HPLC external standard, the yield is 76.8 percent, and the white solid is obtained by column chromatography separation, and the yield is 16.4 percent.
Example 13: preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C in oxygen atmosphere
Magnetons were added to a non-diaphragm electrolytic cell (8mL) at room temperature, followed by disulfide ring-opener a (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. Pumping oxygen by using an oil pump, stirring the reaction liquid for 10min to fully mix when the electrolytic bath is full of oxygen, adjusting a direct current power supply to a constant current mode, and electrolyzing 5F at 8mA until the raw materials are completely converted. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 76.0%.
Example 14: 2 beta-triazole methyl penicillanic acid diphenylmethyl ester C prepared by 2F electric quantity
Magnetons were added to a non-diaphragm cell (8mL) at room temperature, followed byThe disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), and tetrabutylammonium iodide (185mg,0.5mmol,2eq) were added to the vessel. Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution was stirred for 10min for thorough mixing, the DC power was adjusted to constant current mode, and 8mA electrolysis was completed at 2F. After the reaction, the reaction mixture was sampled and subjected to HPLC external standard to obtain a yield of 47.2% and a part of the starting material remained.
Example 15: 8F electric quantity preparation of 2 beta-triazolyl methyl penicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (133mg,0.25mmol),1,2, 3-triazole B (138mg, 2mmol, 8eq), tetrabutylammonium iodide (185mg,0.5mmol,2 eq). Acetonitrile (4.5mL) and acetic acid (0.5mL) were added using a syringe. After all the material has been added, the piece is fitted with graphite flakes (1X 7X 0.3 cm)3) And platinum sheet (1X 7X 0.3 cm)3) The immersion area of the electrode is 2cm2. The reaction solution was stirred for 10min for thorough mixing, the DC power was adjusted to constant current mode, and 8mA electrolysis was completed for 8F. After the reaction, the reaction solution was sampled and subjected to HPLC external standard, and the yield was 59.7%.
Example 16: the current density is 30mA/cm2Preparation of 2 beta-Triazolylmethylpenicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (1000mL), followed by the addition of disulfide ring-opener A (10g,18.8mmol), 1,2, 3-triazole B (10.4g, 150mmol, 8eq), tetrabutylammonium iodide (13.9g,37.6mmol,2 eq). Acetonitrile (340mL,34v) and purified water (40mL,4v) were added using a syringe. After all the materials are added, two graphite plates (3X 8X 0.2 cm) are arranged3) And a nickel plate (3X 8X 0.2 cm)3) The immersion area of the electrode is 3 multiplied by 6 multiplied by 2cm2. Stirring the reaction solution for 10min, mixing thoroughly, and regulating DC power supply to constantCurrent mode, 1080mA electrolysis 5F, IPC detection raw materials conversion is complete. After the reaction is completed, the reaction mixture is concentrated under reduced pressure (>120mbar,35 ℃), adding ethyl acetate and water for extraction and liquid separation, performing back extraction on the water phase by using ethyl acetate, combining organic phases, drying and concentrating to obtain light yellow solid 4.29g, sending internal standard nuclear magnetism to the crude product, and correcting the yield to 43.1%.
Example 17: 10 g-grade preparation of 2 beta-azidomethyl penicillanic acid diphenylmethyl ester C
At room temperature, a magneton was added to a non-diaphragm electrolytic cell (8mL), followed by the addition of disulfide ring-opener A (10g,18.8mmol), 1,2, 3-triazole B (10.4g, 150mmol, 8eq), tetrabutylammonium iodide (13.9g,37.6mmol,2 eq). Acetonitrile (340mL,34v) and purified water (40mL,4v) were added using a syringe. After all the materials are added, two graphite plates (3X 8X 0.2 cm) are arranged3) And a nickel plate (3X 8X 0.2 cm)3) The immersion area of the electrode is 3 multiplied by 6 multiplied by 2cm2. The reaction solution is stirred for 10min and fully mixed, a direct current power supply is adjusted to a constant current mode, 400mA is electrolyzed for 5F, and IPC detects that the raw materials are completely converted. After the reaction is completed, the reaction mixture is concentrated under reduced pressure (>120mbar,35 ℃), adding ethyl acetate and water for extraction and liquid separation, performing back extraction on an aqueous phase by using ethyl acetate, combining organic phases, drying and concentrating to obtain light yellow solid 6.73g, sending internal standard nuclear magnetism to a crude product, and correcting the yield to 73.2%.
Example 18: 30 g-grade preparation of 2 beta-azidomethyl penicillanic acid diphenylmethyl ester C by using flow cell
A magneton was added to the reaction flask at room temperature, followed by disulfide ring-opener A (30g,56.4mmol),1,2, 3-triazole B (31.2g, 451mmol, 8eq), tetrabutylammonium iodide (41.7g,112.8mmol,2 eq). Acetonitrile (1L,34v) and purified water (120mL,4v) were added using a syringe, and the reaction solution was stirred in a reaction flask for 10min to mix well. Flow cell apparatusGraphite plate (18X 12X 0.2 cm)3) And nickel plate (18X 12X 0.2 cm)3) As cathode and anode, the upper and lower reaction chambers are made of polytetrafluoroethylene, and the plate-frame cell electrode area is 13 × 7cm2The flow dead volume between the electrodes was 182 mL. The rubber tube is used for connecting the reaction bottle, the peristaltic pump and the inlet and the outlet of the flow electrolytic tank to form a closed loop. Connecting a power supply and an electrode, adjusting a direct current power supply to a constant current mode, electrolyzing by 1.2A for 5.5F, and detecting by IPC that the raw materials are completely converted. After the reaction is finished, washing the flow tank and the pipeline with a small amount of acetonitrile, combining the reaction solutions, and concentrating under reduced pressure (>120mbar,35 ℃), adding ethyl acetate and water for extraction and liquid separation, performing back extraction on the water phase by using ethyl acetate, combining organic phases, drying and concentrating to obtain light yellow solid 21.6g, sending internal standard nuclear magnetism to the crude product, and correcting the yield to 72.9%.
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 (13)
1. A method for electrochemically synthesizing a tazobactam key intermediate is characterized by comprising the following steps:
taking a disulfide ring-opening compound A and 1,2, 3-triazole B as reaction substrates, mixing the reaction substrates with an electrolyte and a reaction solvent, and then carrying out electrochemical anodic oxidation to obtain a tazobactam key intermediate C; the reaction route of the electrochemical anodic oxidation process is as follows:
the electrolyte comprises an iodine-containing electrolyte, wherein the iodine-containing electrolyte is one or more of tetrabutylammonium iodide, potassium iodide, sodium iodide, zinc iodide, lithium iodide, cuprous iodide and iodine simple substance; when the electrolyte only comprises the iodine-containing electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1.
2. The method for electrochemically synthesizing a tazobactam key intermediate as claimed in claim 1, wherein in the electrochemical anodic oxidation process, the anode used is selected from a carbon rod electrode, a carbon felt electrode, a carbon paper electrode, a carbon cloth electrode, a platinum electrode, an RVC electrode or a BDD electrode; the cathode is selected from nickel, platinum, iron, graphite, gold or silver electrode, and the cathode is sheet, net, rod or wire electrode.
3. The method for electrochemically synthesizing tazobactam key intermediates in accordance with claim 1, wherein the electrolyte further comprises an additional electrolyte selected from one or more of inorganic salts, quaternary ammonium salts and perchlorates.
4. The method for electrochemically synthesizing tazobactam key intermediates in accordance with claim 3, wherein when the electrolyte includes the iodine-containing electrolyte and the additional electrolyte, the molar ratio of the iodine-containing electrolyte to the disulfide ring-opening compound A is 0.18-0.24: 1, and the molar ratio of the additional electrolyte to the disulfide ring-opening compound A is 1.8-2.4: 1.
5. The method for electrochemically synthesizing tazobactam key intermediates in accordance with claim 3, wherein the inorganic salt is selected from one or more of sodium chloride, sodium sulfate, sodium acetate, lithium chloride, potassium sulfate; the quaternary ammonium salt is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium chloride and tetrabutylammonium bromide; the perchlorate is selected from lithium perchlorate and/or sodium perchlorate.
6. The electrochemical synthesis method for tazobactam key intermediate as claimed in any one of claims 1 to 5, wherein the reaction solvent comprises a first solvent and a second solvent, wherein the first solvent is selected from dichloromethane, 1, 2-dichloroethane, ethyl acetateTrichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile,N,N-dimethylformamide,N,N-dimethylacetamide,N,N-diethylformamide,N-one or more of methyl pyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, hexafluoroisopropanol; the second solvent is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid and valeric acid.
7. The method for electrochemically synthesizing a tazobactam key intermediate, according to claim 6, wherein the volume ratio of the first solvent to the second solvent is 1-20: 1.
8. The method for electrochemically synthesizing a tazobactam key intermediate, according to claim 6, wherein the volume ratio of the first solvent to the second solvent is 8-10: 1.
9. The method for electrochemically synthesizing the tazobactam key intermediate according to any one of claims 1 to 5, wherein the molar ratio of the disulfur ring-opening compound A to the 1,2, 3-triazole B in the reaction substrate is 1: 2-20.
10. The method for electrochemically synthesizing the tazobactam key intermediate according to any one of claims 1 to 5, wherein the molar ratio of the disulfur ring-opening compound A to the 1,2, 3-triazole B in the reaction substrate is 1: 7-10.
11. The method for electrochemically synthesizing a tazobactam key intermediate as claimed in any one of claims 1 to 5, wherein the treatment temperature during the electrochemical anodic oxidation is 24-28 ℃.
12. The method for the electrochemical synthesis of tazobactam key intermediates in any one of claims 1 to 5, wherein the electrochemical anodization process isThe method is carried out in a constant current mode, and the current density is 4-30 mA/cm2And the reaction electric quantity in the electrochemical anodic oxidation process is 2-8F.
13. The method for electrochemically synthesizing tazobactam key intermediates in any one of claims 1 to 5, wherein the electrochemical anodic oxidation process is performed in a constant current mode, and the current density is 10-15 mA/cm2The reaction electric quantity in the electrochemical anodic oxidation process is 5-5.5F.
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