CN114276368B - Synthesis method of tazobactam diphenyl methyl ester - Google Patents
Synthesis method of tazobactam diphenyl methyl ester Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- PHGXFQIAGFMIHJ-NWSQWKLXSA-N benzhydryl (2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)(=O)=O)N1C=CN=N1 PHGXFQIAGFMIHJ-NWSQWKLXSA-N 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- -1 tazobactam dibenzoyl ester Chemical class 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- 239000002608 ionic liquid Substances 0.000 claims abstract description 22
- 229960003865 tazobactam Drugs 0.000 claims abstract description 20
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 11
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- HVUUVUMACNYXNA-UHFFFAOYSA-N 4-(2-pyridin-4-ylsulfanylethylsulfanyl)pyridine Chemical compound C=1C=NC=CC=1SCCSC1=CC=NC=C1 HVUUVUMACNYXNA-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 7
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 7
- 229960005055 sodium ascorbate Drugs 0.000 claims description 7
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 6
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000005543 nano-size silicon particle Substances 0.000 claims description 6
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 claims description 3
- MPZMVUQGXAOJIK-UHFFFAOYSA-N 4-bromopyridine;hydron;chloride Chemical compound Cl.BrC1=CC=NC=C1 MPZMVUQGXAOJIK-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 claims description 3
- 239000011343 solid material Substances 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 5
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 abstract description 4
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 abstract description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 abstract description 4
- 150000001540 azides Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 description 4
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical class N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 238000004227 thermal cracking Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of tazobactam dibenzoyl ester. Taking 2 beta-chloromethyl penicillinic acid diphenyl methyl ester, propiolic acid and sodium azide as raw materials, and carrying out one-pot reaction under the catalysis of a catalyst to obtain 2 beta-azido methyl penicillinic acid diphenyl methyl ester; and then oxidizing by potassium permanganate to obtain the product. Compared with the traditional 6-APA route, the invention combines the azide and the cyclization into one-step reaction, adopts a one-pot method to carry out experiments, shortens the reaction time and simplifies the reaction steps; by introducing the nano-supported Cu ionic liquid catalyst as a novel catalyst, the reaction time is reduced, the reaction yield is improved, the catalyst has high recovery rate and can be repeatedly used for a plurality of times, and the production cost is greatly reduced; the propynoic acid is used as the raw material, so that the use of acetylene is avoided, the safety of the reaction can be improved, the reaction condition is mild, the reaction yield is improved, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of tazobactam dibenzoyl ester.
Background
Tazobactam is developed by Japanese Dapeng pharmaceutical company, is a spectrum efficient beta-lactamase inhibitor, and has the characteristics of small toxic and side effect, good stability and high inhibition activity.
According to literature reports, the current synthesis methods of tazobactam can be divided into: penicillin G salt, sulbactam and 6-APA. The most widely used method at present is to use 6-APA as a starting material to obtain tazobactam through steps of bromination, oxidation, esterification, reduction, thermal cracking, chloromethylation, azide, double oxidation, cycloaddition, deprotection and the like, wherein tazobactam diphenyl methyl ester is a product obtained through cycloaddition and is an important intermediate in the reaction process of tazobactam.
How to efficiently introduce the triazacyclo becomes the key of the study of tazobactam dibenzomethyl ester, and the main synthetic route at present is as follows:
route 1:
route 2:
in the scheme 1, acetylene gas is required to be used for high-temperature and high-pressure reaction during cycloaddition, so that the risk is high; in the scheme 2, 2 beta-chloromethyl penicillanic acid diphenyl methyl ester directly reacts with triazole to introduce a triazole ring, and then the target product is prepared by oxidation of potassium permanganate. Although the reaction steps of the route are short, the amount of triazole is large, the recovery is difficult, the yield is low, the cost is high, and the industrial production is not facilitated.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of tazobactam diphenyl methyl ester, which simplifies the reaction steps, shortens the reaction time and has mild reaction conditions, thereby improving the yield of tazobactam diphenyl methyl ester, reducing the cost and improving the safety of the reaction.
The synthesis method of tazobactam diphenyl methyl ester uses 2 beta-chloromethyl penicillinic acid diphenyl methyl ester, propiolic acid and sodium azide as raw materials, and adopts a one-pot method to react under the catalysis of a catalyst to obtain 2 beta-azido methyl penicillinic acid diphenyl methyl ester; and then oxidizing by potassium permanganate to obtain the target product tazobactam dibenzoyl ester.
The synthetic route of the invention is as follows:
the synthesis method of tazobactam dibenzoyl ester comprises the following steps:
(1) Preparation of 2 beta-azidomethyl penicillanic acid diphenyl methyl ester:
adding the nano-supported Cu ionic liquid catalyst and sodium ascorbate into a mixed solution of polyethylene glycol-400 and water, stirring for 15-30 min, adding 2 beta-chloromethyl penicillanic acid diphenyl methyl ester, propiolic acid and sodium azide into a reaction system, stirring at room temperature for reacting for 2-4 h, and performing post-treatment after the reaction is finished to obtain 2 beta-azidomethyl penicillanic acid diphenyl methyl ester;
(2) Preparation of tazobactam dibenzoyl ester:
dissolving 2 beta-azidomethyl penicillanic acid diphenyl methyl ester in a mixed solution of water and glacial acetic acid, cooling to-10-0 ℃, adding potassium permanganate, heating to 10-25 ℃, carrying out heat preservation reaction for 2-5 h, cooling to below 10 ℃, beginning to dropwise add hydrogen peroxide until the material liquid is clear, standing for layering, carrying out reduced pressure distillation on the obtained organic phase to obtain oily matter, and finally adding methanol for crystallization to obtain tazobactam diphenyl methyl ester.
Wherein:
in the step (1), the nano-supported Cu ionic liquid catalyst is prepared by the following method:
(1) Preparation of nanosilicon dioxide
Preparing a mixed solution of n-amyl alcohol and sodium dodecyl benzene sulfonate, adding cyclohexane, carrying out ultrasonic vibration uniformly, then transferring water, stirring at room temperature, and finally adding tetraethoxysilane for continuous reaction; centrifuging, washing with ethanol, and vacuum drying to obtain nanometer silica;
(2) Preparation of 1, 2-bis (4-pyridylthio) ethane
Adding 4-bromopyridine hydrochloride, 1, 2-ethanedithiol and sodium hydroxide into DMF for reaction; after the reaction is finished, adding a certain amount of water and ethyl acetate into the reaction solution, filtering, extracting and layering the filtrate to obtain a water phase and an organic phase, concentrating the water phase under reduced pressure, and finally recrystallizing the obtained concentrate with methanol to obtain 1, 2-bis (4-pyridylthio) ethane;
(3) Preparation of supported nano ionic liquid
Adding nano silicon dioxide, 1, 2-bis (4-pyridylthio) ethane and DMF into a container, condensing and refluxing, centrifuging the reaction liquid, washing the obtained solid product with methanol, and drying; mixing the dried powder with toluene, adding the mixture into methyl iodide, stirring at room temperature for reaction, centrifuging after the reaction is finished, washing a product with petroleum ether, and drying the product to obtain the supported nano ionic liquid;
(4) Preparation of load type nano Cu ion liquid
Cu (OTF) 2 Adding the loaded nano ionic liquid into ethanol for reflux; and after the reaction is finished, centrifuging the reaction liquid, washing the obtained solid material with ethanol, and drying to obtain the supported nano Cu ionic liquid.
In the step (1), the volume ratio of the polyethylene glycol-400 to the water is 1-2:1.
In step (1), 2 beta-chloromethyl penicillanic acid dibenzoyl ester: propiolic acid: sodium azide: sodium ascorbate: the molar ratio of the catalyst is as follows: 1:1-2:1-1.5:0.2-0.4:0.1-0.5.
In the step (1), after the reaction is finished, ethyl acetate is added, the mixture is centrifuged, and the obtained catalyst is rinsed by acetone and water and dried for repeated use; the organic phase was separated and dehydrated with anhydrous magnesium sulfate and recrystallized from ethanol.
In the step (2), the volume ratio of water to glacial acetic acid is 1:1-2.
In the step (2), the mass volume ratio of the 2 beta-azidomethyl penicillanic acid diphenyl methyl ester to the mixed solution of water and glacial acetic acid is 1:3-4 g/mL.
In the step (2), the molar ratio of the 2 beta-azidomethyl penicillanic acid diphenyl methyl ester to the potassium permanganate is 1:1-3.
Compared with the prior art, the invention has the following beneficial effects:
(1) Compared with the traditional 6-APA route, the method combines the azide and the cyclization addition into one-step reaction, adopts a one-pot method to carry out experiments, shortens the reaction time and simplifies the reaction steps;
(2) By introducing the nano-supported Cu ionic liquid catalyst as a novel catalyst, the reaction time is reduced, the reaction yield is improved, the catalyst recovery rate is high, only the loss is needed to be supplemented, and the production cost is greatly reduced;
(3) The propynoic acid is used as the raw material, so that the use of acetylene is avoided, the safety of the reaction can be improved, the reaction condition is mild, the reaction can be carried out at normal temperature and normal pressure, the reaction yield is improved, and the method is suitable for large-scale industrial production.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are commercially available from the public unless otherwise specified.
The catalyst adopted in the following examples is a nano-supported Cu ionic liquid catalyst, and the preparation method thereof is as follows:
(1) Preparation of nanosilicon dioxide
N-amyl alcohol (35 ml) and sodium dodecyl benzene sulfonate (35 g) mixed solution are prepared, cyclohexane (165 ml) is added, ultrasonic oscillation is carried out uniformly, water (10 ml) is added, stirring is carried out for 30min at room temperature, and finally tetraethoxysilane is added for continuous reaction. Centrifuging, washing with ethanol, and vacuum drying at 100deg.C for 2 hr to obtain nanometer silica.
(2) Preparation of 1, 2-bis (4-pyridylthio) ethane
4-bromopyridine hydrochloride (1 g), 1, 2-ethanedithiol (0.3 ml), sodium hydroxide (0.3 g) were added to DMF (10 ml) and reacted at 80℃for 24 hours; after the reaction, 10ml of water and 10ml of ethyl acetate were added to the reaction solution and filtered, the filtrate was subjected to extraction and delamination to obtain an aqueous phase and an organic phase, the aqueous phase was concentrated under reduced pressure, and finally the obtained concentrate was recrystallized from methanol to obtain 1, 2-bis (4-pyridylthio) ethane.
(3) Preparation of supported nano ionic liquid
Nano silicon dioxide (5.0 g), 1, 2-di (4-pyridylthio) ethane (2 g) and DMF (60 ml) are added into a round bottom flask, condensed and refluxed at 80 ℃ for 6 hours, the reaction liquid is centrifuged, and the obtained solid product is washed by methanol and dried at 40 ℃; mixing 5g of dried powder with toluene (50 ml), adding into methyl iodide (2.5 g) at room temperature, stirring for reaction, centrifuging after the reaction is finished, washing a product with petroleum ether, and drying the product at 60 ℃ to obtain the supported nano ionic liquid.
(4) Preparation of load type nano Cu ion liquid
Cu (OTF) 2 (20 mg) and the supported nano ionic liquid (5 g) are added into ethanol (50 ml) to reflux for 24h. And after the reaction is finished, centrifuging the reaction solution, washing the obtained solid material with ethanol, and drying at 60 ℃ to obtain the supported nano Cu ionic liquid.
Example 1
(1) Preparation of 2 beta-azidomethyl penicillanic acid diphenyl methyl ester
0.01mol of nano-supported Cu ionic liquid catalyst and 0.02mol of sodium ascorbate are added into polyethylene glycol-400/water (1:1, 200 mL) and stirred for 15min, and 42g (0.1 mol) of 2 beta-chloromethyl penicillinic acid diphenyl methyl ester and 7.8g (0.12 mol) of NaN are added 3 And 7g (0.1 mol) of propiolic acid are added into the reaction system, stirred at room temperature for 2.5h, 200mL of ethyl acetate is added after the reaction is finished, and the obtained catalyst is washed with acetone and water and dried for repeated use; the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and recrystallized from ethanol to give 40.9g of 2 beta-azidomethyl penicillanic acid dibenzoyl ester in a yield of 90.4% [ calculated as 2 beta-chloromethyl penicillanic acid dibenzoyl ester, yield = dry weight/(2 beta-chloromethyl penicillanic acid dibenzoyl ester mass x 1.077)]。
(2) Preparation of tazobactam dibenzoyl ester
Dissolving 40.9g (0.09 mol) of 2 beta-azidomethyl penicillanic acid dibenzoyl ester obtained in the step (1) in 150mL of ethyl acetate, adding 50mL of glacial acetic acid and 50mL of water, cooling to 0 ℃, slowly adding 28.4g (0.18 mol) of potassium permanganate in batches, heating to 20 ℃ after the addition is finished, preserving heat for 3 hours, cooling to 5 ℃, dropwise adding hydrogen peroxide into a reaction liquid until the liquid is clarified, standing for layering, decompressing and distilling the obtained organic phase, filtering, obtaining a crude product, and recrystallizing with methanol to obtain 39g of white solid with the yield of 89.1 percent (calculated by 2 beta-azidomethyl penicillanic acid dibenzoyl ester, and the yield is calculated as dry product weight/(2 beta-azidomethyl penicillanic acid dibenzoyl ester mass multiplied by 1.070).
Example 2
(1) Preparation of 2 beta-azidomethyl penicillanic acid diphenyl methyl ester
0.03mol of nano-supported Cu ionic liquid catalyst and 0.03mol of sodium ascorbate are added into polyethylene glycol-400/water (1.5:1, 200 mL) and stirred for 20min, and 42g (0.1 mol) of 2 beta-chloromethyl penicillanic acid diphenyl methyl ester and 8.5g (0.13 mol) of NaN are added 3 And 10.5g (0.15 mol) of propiolic acid are added into the reaction system, stirred at room temperature for reaction for 3 hours, 200mL of ethyl acetate is added after the reaction is finished, and the obtained catalyst is washed with acetone and water and dried for repeated use; the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and recrystallized from ethanol to give 41.2g of 2 beta-azidomethyl penicillanic acid dibenzoyl ester in 91.09% yield [ calculated as 2 beta-chloromethyl penicillanic acid dibenzoyl ester, yield = dry weight/(2 beta-chloromethyl penicillanic acid dibenzoyl ester mass x 1.077)]。
(2) Preparation of tazobactam dibenzoyl ester
Dissolving 41.2g (0.09 mol) of 2 beta-azidomethyl penicillanic acid dibenzoyl ester obtained in the step (1) in 150mL of ethyl acetate, adding 75mL of glacial acetic acid and 50mL of water, cooling to-5 ℃, slowly adding 23.7g (0.15 mol) of potassium permanganate in batches, heating to 25 ℃ after the addition is finished, preserving heat for 4 hours, cooling to 3 ℃, dropwise adding hydrogen peroxide into a reaction liquid until the liquid is clarified, standing for layering, decompressing an obtained organic phase, distilling, filtering, obtaining a crude product, recrystallizing with methanol to obtain 39.5g of white solid with the yield of 89.6 percent (calculated by 2 beta-azidomethyl penicillanic acid dibenzoyl ester, and obtaining the yield = dry weight/(2 beta-azidomethyl penicillanic acid dibenzoyl ester mass multiplied by 1.070) ].
Example 3
(1) Preparation of 2 beta-azidomethyl penicillanic acid diphenyl methyl ester
Adding 0.05mol of nano-supported Cu ionic liquid catalyst and 0.04mol of sodium ascorbate into polyethylene glycolStirring in alcohol-400/water (2:1, 200 mL) for 30min, followed by 42g (0.1 mol) of 2 beta-chloromethyl penicillanic acid dibenzoyl ester, 9.7g (0.15 mol) of NaN 3 And 14g (0.2 mol) of propiolic acid are added into the reaction system, stirred at room temperature for reaction for 3.5h, 200mL of ethyl acetate is added after the reaction is finished, and the obtained catalyst is washed with acetone and water and dried for repeated use; the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and recrystallized from ethanol to give 40.6g of 2 beta-azidomethyl penicillanic acid dibenzoyl ester in 89.7% yield [ calculated as 2 beta-chloromethyl penicillanic acid dibenzoyl ester, yield = dry weight/(2 beta-chloromethyl penicillanic acid dibenzoyl ester mass x 1.077)]。
(2) Preparation of tazobactam dibenzoyl ester
Dissolving 40.6g (0.089 mol) of 2 beta-azidomethyl penicillanic acid dibenzoyl ester obtained in the step (1) in 150mL of ethyl acetate, adding 100mL of glacial acetic acid and 50mL of water, cooling to-8 ℃, slowly adding 31.6g (0.2 mol) of potassium permanganate in batches, heating to 15 ℃ after the addition is finished, preserving heat for 4 hours, cooling to 0 ℃, dropwise adding hydrogen peroxide into a reaction liquid until the liquid is clear, standing for layering, decompressing and distilling an obtained organic phase, filtering, obtaining a crude product, recrystallizing with methanol to obtain 38.5g of white solid with the yield of 88.6 percent (calculated by 2 beta-azidomethyl penicillanic acid dibenzoyl ester, and obtaining the yield = dry weight/(2 beta-azidomethyl penicillanic acid dibenzoyl ester mass multiplied by 1.070) ].
Comparative example 1
41.11g (0.095 mol) of 2 alpha-methyl-2 beta- (1, 2, 3-triazole-1-yl) methyl-3 alpha-carboxylic acid dibenzoyl ester is dissolved in 35mL of acetone, 70mL of water and 105mL of glacial acetic acid are added, the mixture is cooled to 0 to 5 ℃ and KMnO is added under stirring 4 The mixture was treated with 5mol. L -1 The pH was adjusted to 6.5, and the reaction was stirred at room temperature for 3 hours. 30% hydrogen peroxide is added dropwise until the reaction liquid is colorless, the reaction liquid is filtered, and the obtained crude product is recrystallized by methanol to obtain 37.2g tazobactam dibenzoyl methyl ester with the yield of 84%.
Comparative example 2
10g of intermediate 2 beta-azidomethyl penicillanate diphenyl methyl ester-1, 1-dioxide is dissolved in 80ml of ethyl acetate, the mixture is put into an autoclave, acetylene is introduced and the pressure is kept between 1.8 and 2.0kg/cm 2 Heating to 80-85 deg.C, maintaining the temperature for 48 hr, cooling to 0-5 deg.C, crystallizing for 2-3 hr, filtering, and drying to obtain tazobactam dibenzoyl ester 9g with yield of 85%.
Specific examples have been provided herein to illustrate the principles and embodiments of the present invention and are provided to assist in understanding the core concepts of the invention. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (4)
1. A synthesis method of tazobactam diphenyl methyl ester is characterized by comprising the following steps: taking 2 beta-chloromethyl penicillanic acid diphenyl methyl ester, propiolic acid and sodium azide as raw materials, and reacting by adopting a one-pot method under the catalysis of a catalyst to obtain 2 beta- (1, 2, 3-triazole-1-yl) methyl penicillanic acid diphenyl methyl ester; then oxidizing by potassium permanganate to obtain a target product tazobactam dibenzoyl ester;
the method specifically comprises the following steps:
(1) The preparation of 2 beta- (1, 2, 3-triazole-1-yl) methyl penicillanic acid diphenyl methyl ester comprises the following steps:
adding a nano-supported Cu ionic liquid catalyst and sodium ascorbate into a mixed solution of polyethylene glycol-400 and water, stirring for 15-30 min, adding 2 beta-chloromethyl penicillanic acid dibenzoyl ester, propiolic acid and sodium azide into a reaction system, stirring at room temperature for reacting for 2-4 h, and performing post-treatment after the reaction is finished to obtain 2 beta- (1, 2, 3-triazole-1-yl) methylpenicillinic acid dibenzoyl ester;
(2) Preparation of tazobactam dibenzoyl ester:
dissolving 2 beta- (1, 2, 3-triazole-1-yl) methyl penicillanic acid diphenyl methyl ester in a mixed solution of water and glacial acetic acid, cooling to-10-0 ℃, adding potassium permanganate, heating to 10-25 ℃, carrying out heat preservation reaction for 2-5 h, cooling to below 10 ℃, beginning to dropwise add hydrogen peroxide until the feed liquid is clarified, standing for layering, carrying out reduced pressure distillation on an obtained organic phase to obtain oily matter, and finally adding methanol for crystallization to obtain tazobactam diphenyl methyl ester;
in the step (1), the nano-supported Cu ionic liquid catalyst is prepared by the following method:
(1) Preparation of nanosilicon dioxide
Preparing a mixed solution of n-amyl alcohol and sodium dodecyl benzene sulfonate, adding cyclohexane, carrying out ultrasonic vibration uniformly, then transferring water, stirring at room temperature, and finally adding tetraethoxysilane for continuous reaction; centrifuging, washing with ethanol, and vacuum drying to obtain nanometer silica;
(2) Preparation of 1, 2-bis (4-pyridylthio) ethane
Adding 4-bromopyridine hydrochloride, 1, 2-ethanedithiol and sodium hydroxide into DMF for reaction; after the reaction is finished, adding a certain amount of water and ethyl acetate into the reaction solution, filtering, extracting and layering the filtrate to obtain a water phase and an organic phase, concentrating the water phase under reduced pressure, and finally recrystallizing the obtained concentrate with methanol to obtain 1, 2-bis (4-pyridylthio) ethane;
(3) Preparation of supported nano ionic liquid
Adding nano silicon dioxide, 1, 2-bis (4-pyridylthio) ethane and DMF into a container, condensing and refluxing, centrifuging the reaction liquid, washing the obtained solid product with methanol, and drying; mixing the dried powder with toluene, adding the mixture into methyl iodide, stirring at room temperature for reaction, centrifuging after the reaction is finished, washing a product with petroleum ether, and drying the product to obtain the supported nano ionic liquid;
(4) Preparation of load type nano Cu ion liquid
Cu (OTF) 2 Adding the loaded nano ionic liquid into ethanol for reflux; after the reaction is finished, centrifuging the reaction liquid, washing the obtained solid material with ethanol, and drying to obtain the supported nano Cu ionic liquid;
in the step (1), the volume ratio of polyethylene glycol-400 to water is 1-2:1;
in step (1), 2 beta-chloromethyl penicillanic acid dibenzoyl ester: propiolic acid: sodium azide: sodium ascorbate: the molar ratio of the catalyst is as follows: 1:1-2:1-1.5:0.2-0.4:0.1-0.5;
in the step (1), after the reaction is finished, ethyl acetate is added, the mixture is centrifuged, and the obtained catalyst is rinsed by acetone and water and dried for repeated use; the organic phase was separated and dehydrated with anhydrous magnesium sulfate and recrystallized from ethanol.
2. The synthesis method of tazobactam dibenzoate according to claim 1, wherein: in the step (2), the volume ratio of water to glacial acetic acid is 1:1-2.
3. The synthesis method of tazobactam dibenzoate according to claim 1, wherein: in the step (2), the mass volume ratio of the 2 beta- (1, 2, 3-triazole-1-yl) methyl penicillanic acid dibenzoyl ester to the mixed solution of water and glacial acetic acid is 1:3-4 g/mL.
4. The synthesis method of tazobactam dibenzoate according to claim 1, wherein: in the step (2), the molar ratio of 2 beta- (1, 2, 3-triazole-1-yl) methyl penicillanic acid dibenzoyl ester to potassium permanganate is 1:1-3.
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