CN113861222A - Method for synthesizing desoxytazobactam diphenylmethyl ester by adopting novel catalyst - Google Patents
Method for synthesizing desoxytazobactam diphenylmethyl ester by adopting novel catalyst Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1616—Coordination complexes, e.g. organometallic complexes, immobilised on an inorganic support, e.g. ship-in-a-bottle type catalysts
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1691—Coordination polymers, e.g. metal-organic frameworks [MOF]
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/40—Complexes comprising metals of Group IV (IVA or IVB) as the central metal
- B01J2531/42—Tin
Abstract
The invention discloses a method for synthesizing desoxytazobactam diphenylmethyl ester by adopting a novel catalyst. According to the invention, firstly, a solvent thermal method is adopted to prepare the bimetal coordination polymer, then silica gel is used as a carrier, the prepared bimetal coordination polymer is loaded in a pore channel of the silica gel and is better stabilized in the pore channel through metal reduction, the reduction of active sites caused by reaction is prevented, and the stability and the recyclability of the catalyst are improved, so that the alkalescent loaded bimetal porous coordination polymer catalyst which can be repeatedly used, has stronger activity and good stability is obtained. The deoxidized tazobactam diphenylmethyl ester is synthesized by adopting the catalyst, and a two-phase system of acetone and water is adopted in the reaction, so that the reaction time of triazole is greatly shortened, side reactions are reduced, and the product yield can reach 82-86%.
Description
Technical Field
The invention relates to a method for synthesizing desoxytazobactam diphenylmethyl ester by adopting a novel catalyst, belonging to the technical field of medicine preparation.
Background
Tazobactam is a novel, broad-spectrum and high-efficiency beta-lactamase inhibitor of the penicillanesulfone, is developed successfully by the pharmaceutical company of Japan Roc at the earliest, and has the characteristics of low toxicity, good stability, broad-spectrum beta-lactamase inhibition effect and the like. Currently, tazobactam/piperacillin (1:8) compound preparations are mainly used clinically for treating various bacterial infections. Tazobactam, molecular formula: c10H12N4O5S, molecular weight 300.29; chemical name: (2S,3S,5R) -3-methyl-7-oxo-3- (1H-l,2, 3-triazol-1-ylmethyl) -4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylic acid-4, 4-dioxide, the structural formula is as follows.
The synthesis methods of tazobactam are reported at present, and two synthesis routes suitable for large-scale production are mainly provided:
the first synthetic route is as follows: the 2 beta-chloromethyl penicillanic acid diphenylmethyl ester is prepared through the steps of azide, oxidation, cyclization, deprotection and the like, for example, the synthetic method of tazobactam disclosed in CN102643292A, and the synthetic route is shown as follows. The azide process of the synthetic route uses flammable and explosive or highly toxic reagents, such as sodium azide and acetylene, which causes the production process to be dangerous.
The second synthetic route is as follows: the 2 beta-chloromethyl penicillanic acid diphenylmethyl ester is directly prepared by the steps of condensation with triazole, oxidation, deprotection and the like, for example, the synthetic method of tazobactam/tazobactam sodium disclosed by CN108164550A and CN101434610A has the following synthetic route.
The triazole process method of the synthesis route II is a hot spot of recent tazobactam synthesis, sodium azide and acetylene are not needed in the synthesis route, the dangerous operation of high temperature and high pressure is avoided, the use of flammable and explosive reagents is also avoided, but the reaction time of the triazole process is long, and meanwhile, because chloride ions of 2 beta-chloromethyl penicillanic acid diphenylmethyl ester are easily removed under the influence of sulfur atom lone pair electrons and are attacked by nucleophilic ions in 1H-1,2, 3-triazole under the alkaline action, the generated carbenium ions are easily rearranged, the probability of generating six-membered ring byproducts is high, and the yield is low. The route reported in CN104031065A improves the stability of sulfur atoms by mono-oxidation, but increases the reaction step (mono-oxidation).
In order to reduce the reaction time of the triazole process, a catalyst may be appropriately added to promote the reaction. At present, catalysts used in the method are mainly sodium iodide, basic resin and the like, but the catalysts have the defects of low activity, incapability of being repeatedly used or need to be regenerated and the like.
Disclosure of Invention
In order to solve the problems, the invention provides a method for synthesizing desoxytazobactam diphenylmethyl ester by using a novel catalyst. According to the invention, firstly, a solvent thermal method is adopted to prepare the bimetal coordination polymer, then silica gel is used as a carrier, the prepared bimetal coordination polymer is loaded in a pore channel of the silica gel and is better stabilized in the pore channel through metal reduction, the reduction of active sites caused by reaction is prevented, and the stability and the recyclability of the catalyst are improved, so that the alkalescent loaded bimetal porous coordination polymer catalyst which can be repeatedly used, has stronger activity and good stability is obtained. The deoxidized tazobactam diphenylmethyl ester is synthesized by adopting the catalyst, and a two-phase system of acetone and water is adopted in the reaction, so that the reaction time of triazole is greatly shortened, side reactions are reduced, and the product yield can reach 82-86%.
The invention firstly provides a preparation method of a alkalescent load type bimetal porous coordination polymer catalyst, which is characterized in that,
(1) dissolving copper chloride and stannic chloride in water, adding pyridine (or 2, 2-bipyridine), imidazole and Dimethylformamide (DMF), uniformly mixing, adjusting the pH value of the solution to 8.5-9.5, carrying out hydrothermal reaction at the temperature of 80-85 ℃, and after the reaction is finished, carrying out suction filtration, washing a filter cake, drying and grinding to obtain a bimetal coordination polymer;
(2) completely dissolving the bimetal coordination polymer by using purified water and dilute nitric acid, adjusting the pH value of the solution to 9-10, adding silica gel, stirring at 50-55 ℃, cooling to room temperature, slowly adding solid sodium borohydride, performing suction filtration, washing a filter cake, drying and grinding to obtain the alkalescent supported bimetal porous coordination polymer catalyst.
The molar ratio of the materials in the step (1) is pyridine (or 2, 2-bipyridine): copper chloride: tin tetrachloride: imidazole is 1 (0.7-1.0): (1.0-1.2): (1.3-1.7), preferably 1:0.8:1.1: 1.5. The volume ratio of the water to the DMF is 1: 0.8-1.2, and preferably 1:1. The hydrothermal reaction time of the step (1) is 4-5 h.
The amount of the sodium borohydride added in the step (2) is 2-5% of the mass of the bimetallic coordination polymer. The dosage of the silica gel is 1-2 times, preferably 1.1-1.3 times of the mass of the bimetallic coordination polymer; after the purified water and the dilute nitric acid are mixed, the concentration of the nitric acid is 0.1-0.5 mol/L. And (3) adding silica gel and stirring for 3-4 h.
The invention also provides the application of the catalyst in synthesizing the desoxytazobactam diphenylmethyl ester.
The invention also provides a method for synthesizing desoxytazobactam diphenylmethyl ester by adopting the novel catalyst, which is characterized in that 2 beta-chloromethyl penicillanic acid diphenylmethyl ester is added into acetone for dissolving, then water, triazole and a weakly alkaline load type bimetal porous coordination polymer catalyst are added, and the temperature is controlled to be 10-20 ℃ for reaction for 3-5 h; after the reaction is finished, carrying out suction filtration (catalyst removal), washing the filtrate with water, evaporating to dryness, and adding acetone and n-hexane for recrystallization to obtain the desoxytazobactam diphenylmethyl ester. The synthetic route is as follows:
in the above reaction, the mass ratio of 2 β -chloromethyl penicillanic acid diphenylmethyl ester: triazole: acetone: water is 1 (0.3 to 0.7) to 0.5 to 0.7 (0.15 to 0.25), preferably 1:0.5:0.6: 0.2.
In the reaction, the dosage of the catalyst is 0.5 to 1 percent of the weight of the 2 beta-chloromethyl penicillanic acid diphenylmethyl ester.
The acetone and n-hexane are recrystallized into the following components: firstly adding acetone for dissolving, then dropwise adding n-hexane until solid is separated out, and then stirring at room temperature for 0.5-1 h; and cooling to-5-0 ℃ for crystallization for 2-3 h, carrying out suction filtration, washing the precipitated solid, and drying to obtain the desoxytazobactam diphenylmethyl ester. The volume ratio of the acetone to the n-hexane is 1: 0.1-0.2.
The invention has the beneficial effects that:
1. according to the invention, a solvent thermal method is adopted to prepare the bimetallic coordination polymer, and the ligand used by the bimetallic coordination polymer is pyridine or 2, 2-bipyridine and imidazole, so that the catalyst is weakly alkaline, and has more alkaline active sites and higher thermal stability. Then, silica gel is used as a carrier, so that the stability and repeated applicability of the catalyst are enhanced. The prepared bimetal coordination polymer is loaded in the pore canal of the silica gel and then is better stabilized in the pore canal by metal reduction (NaBH is utilized)4Dissociated H-The nucleophilic addition is carried out on the positive charge center of the metal, so that metal ions are reduced to 0-valent metal, and the metal is wrapped in the pore channel of the carrier), the reduction of active sites caused by the reaction is prevented, the stability and the recyclability of the catalyst are improved, and the alkalescent supported bimetal porous coordination polymer catalyst which can be repeatedly used, has stronger activity and good stability is obtained.
2. The catalyst prepared by the invention has a plurality of active sites, so that the reaction time of triazole is greatly shortened, side reactions are reduced, and meanwhile, a two-phase system of acetone and water is adopted in the reaction, and the reaction system is homogeneous by controlling the raw material ratio, so that the reaction speed is accelerated (the reaction time is shortened), the production efficiency is improved, the product yield can reach 82-86%, and the catalyst has wide economic benefits and production prospects.
Drawings
FIG. 1 is a process flow diagram for synthesizing desoxytazobactam diphenylmethyl ester by using a novel catalyst.
Detailed Description
The present invention is further illustrated by the following examples. The process flow diagram is shown in figure 1.
Example 1:
(1) under the condition of room temperature, adding 10.8g (0.08mol) of copper chloride, 28.7g (0.11mol) of stannic chloride and 300ml of water into a 1000ml beaker, completely dissolving, then adding 7.9g (0.1mol) of pyridine, 10.2g (0.15mol) of imidazole and 300ml of Dimethylformamide (DMF), uniformly mixing, adjusting the pH value of the solution to 8.5-9.5 (the concentration is 15-20% ammonia water), transferring the solution into a 1000ml polytetrafluoroethylene reaction kettle after the preparation is finished, putting the solution into an oven, carrying out temperature programming to 80-85 ℃, carrying out heat preservation for 4-5 h after the temperature is raised to 80 ℃, and carrying out temperature programming to room temperature. And (3) carrying out suction filtration on the reacted feed liquid, washing a filter cake to be neutral (about pH 7) by using 50ml of water and 20ml of DMF (dimethyl formamide), obtaining a solid 1, putting the solid 1 into an oven, setting the temperature to be 60 ℃, carrying out vacuum drying for 4h, and then grinding the obtained dried solid to obtain 52.1g (dried) of the bimetal coordination polymer 1 with the granularity of 200 meshes and 300 meshes for later use.
(2) At 50-55 ℃, after 52.1g of the bimetallic coordination polymer is completely dissolved by 300ml of purified water and 6mol/L of 12.5g of nitric acid, the pH of the solution is adjusted to 9-10 (22-25% ammonia water is used), 60g of 100-mesh silica gel is added, and the mixture is stirred for 3-4 hours. After cooling to room temperature, slowly adding 2.4g of sodium borohydride and 20ml of water, stirring, carrying out suction filtration, washing a filter cake with 50ml of purified water, putting the solid into an oven, setting the temperature to be 60 ℃, and carrying out vacuum drying for 4 hours. Then the obtained dried solid is ground, the granularity is 200-300 meshes, and 106.8g (dried) weakly alkaline load type bimetal porous coordination polymer 1 is obtained.
(3) Dissolving 60g of 2 beta-chloromethyl penicillanic acid diphenylmethyl ester by 36.2g of acetone, adding 12.5g of water and 30.5g of 1H-1,2, 3-triazole, controlling the temperature to be 15-20 ℃ and reacting for 4-5H, wherein the alkalescent load type bimetal porous coordination polymer 1 obtained in the step (2) is added in three times in the reaction process, and the dosage is 0.45 g.
(4) The reacted feed liquid is pumped and filtered, and the filter cake (catalyst) is washed for the next time. The resulting centrifuged mother liquor was washed three times with 100ml of water and evaporated under reduced pressure until no liquid flowed out. Adding 30g of acetone for dissolution, and stirring at room temperature for 0.5-1 h; dropwise adding 4.5g of n-hexane until solid is separated out, and stirring at room temperature for 0.5-1 h; and cooling to-5-0 ℃ for crystallization for 2-3 h, performing suction filtration, washing the precipitated solid, and drying to obtain 54.5g of desoxytazobactam diphenylmethyl ester, wherein the product purity is 98.7%, and the yield of the dried product is 83.9%.
If the catalyst is recovered and used next time, activation treatment is not needed, and the number of alkaline sites is large. And (4) after about twenty batches of the raw materials are mechanically used, soaking and washing the raw materials in alkaline (ammonia water with the concentration of 15-25%), drying and grinding the raw materials for later use.
Example 2:
(1) under the condition of room temperature, adding 5.4g (0.04mol) of copper chloride, 14.4g (0.055mol) of stannic chloride and 200ml of water into a 1000ml beaker, completely dissolving, then adding 7.8g (0.05mol) of 2, 2-bipyridine, 5.1g (0.075mol) of imidazole and 200ml of Dimethylformamide (DMF), uniformly mixing, adjusting the pH value of the solution to 8.5-9.5 (the concentration is 15-20% ammonia), transferring the solution into a 1000ml polytetrafluoroethylene reaction kettle after the preparation is finished, putting the solution into an oven, raising the temperature to 80-85 ℃, carrying out heat preservation hydrothermal reaction for 4-5 h after the temperature is raised to 80 ℃, and then carrying out programmed cooling to room temperature; and (3) carrying out suction filtration on the reacted feed liquid, washing a filter cake to be neutral by using 50ml of water and DMF20ml to obtain a solid 2, putting the solid 2 into an oven, setting the temperature to be 60 ℃, and carrying out vacuum drying for 4 hours. The obtained dried solid was ground to a particle size of 200-300 mesh to obtain 31.5g (dried) of the bimetallic coordination polymer 2 for use.
(2) At 50-55 ℃, after 31.5g of the bimetal coordination polymer is completely dissolved by 200ml of purified water and 6mol/L of 8g of nitric acid, the pH of the solution is adjusted to 9-10 (22-25% ammonia water is used), 40g of 100-mesh silica gel is added, and the mixture is stirred for 3-4 hours. After cooling to room temperature, slowly adding 1.7g of sodium borohydride and 15ml of water, carrying out suction filtration, washing a filter cake with 50ml of purified water, putting the solid into an oven, setting the temperature to be 60 ℃, and carrying out vacuum drying for 4 hours. Then, the obtained dried solid is ground, the particle size is 200-300 meshes, and 68.9g (dried) weakly alkaline load type bimetal porous coordination polymer 2 is obtained.
(3) Dissolving 80g of 2 beta-chloromethyl penicillanic acid diphenylmethyl ester by using 48g of acetone, adding 16g of water and 40.5g of 1H-1,2, 3-triazole, controlling the temperature to be 15-20 ℃ and reacting for 4-5H, wherein the alkalescent load type bimetal porous coordination polymer obtained in the step (2) is added for 2 times in the reaction process, and the using amount is 0.6 g.
(4) The reacted feed liquid is pumped and filtered, and the filter cake (catalyst) is washed for the next time. The resulting centrifuged mother liquor was washed three times with 100ml of water and evaporated under reduced pressure until no liquid flowed out. Adding 40g of acetone for dissolution, and stirring at room temperature for 0.5-1 h; dropwise adding 5.8g of n-hexane until solid is separated out, and stirring at room temperature for 0.5-1 h; and cooling to-5-0 ℃ for crystallization for 2-3 h, performing suction filtration, washing the precipitated solid, and drying to obtain 73.0g of desoxytazobactam diphenylmethyl ester, wherein the product purity is 98.5%, and the yield of the product obtained after drying is 84.3%.
Claims (10)
1. A preparation method of a weakly alkaline load type bimetal porous coordination polymer catalyst is characterized in that,
(1) dissolving copper chloride and stannic chloride in water, adding pyridine or 2, 2-bipyridine, imidazole and dimethylformamide, mixing uniformly, adjusting the pH value of the solution to 8.5-9.5, carrying out hydrothermal reaction at the temperature of 80-85 ℃, and after the reaction is finished, carrying out suction filtration, filter cake washing, drying and grinding to obtain the bimetal coordination polymer;
(2) completely dissolving the bimetal coordination polymer by using purified water and dilute nitric acid, adjusting the pH value of the solution to 9-10, adding silica gel, stirring at 50-55 ℃, cooling to room temperature, slowly adding a sodium borohydride aqueous solution, performing suction filtration, washing a filter cake, drying and grinding to obtain the alkalescent supported bimetal porous coordination polymer catalyst.
2. The method for preparing a weakly basic supported bimetallic porous coordination polymer catalyst as claimed in claim 1, wherein the molar ratio of the materials in step (1) is pyridine or 2, 2-bipyridine: copper chloride: tin tetrachloride: 1 (0.7-1.0) to 1.0 to 1.2 to 1.3-1.7) of imidazole; the volume ratio of the water to the DMF is 1: 0.8-1.2.
3. The method for preparing the weakly basic supported bimetallic porous coordination polymer catalyst as claimed in claim 1, wherein the amount of the sodium borohydride added in the step (2) is 2-5% of the amount of the bimetallic coordination polymer; the dosage of the silica gel is 1-2 times of the mass of the bimetallic coordination polymer; after the purified water and the dilute nitric acid are mixed, the concentration of the nitric acid is 0.1-0.5 mol/L.
4. The preparation method of the weakly basic supported bimetal porous coordination polymer catalyst as claimed in claim 1, wherein the hydrothermal reaction time in the step (1) is 4-5 h; and (3) adding silica gel and stirring for 3-4 h.
5. A weakly basic supported bimetallic porous coordination polymer catalyst prepared by the process of any one of claims 1-4.
6. The use of the weakly basic supported bimetallic porous coordination polymer catalyst of claim 5 in the synthesis of desoxytazobactam diphenylmethyl ester.
7. A method for synthesizing desoxytazobactam diphenylmethyl ester by using the catalyst of claim 5 is characterized in that 2 beta-chloromethyl penicillanic acid diphenylmethyl ester is added into acetone for dissolving, then water, triazole and a weakly alkaline supported bimetallic porous coordination polymer catalyst are added, and the temperature is controlled to be 10-20 ℃ for reaction for 3-5 hours; after the reaction is finished, removing the catalyst by suction filtration, washing the filtrate with water, evaporating to dryness, and adding acetone and n-hexane for recrystallization to obtain the desoxytazobactam diphenylmethyl ester.
8. The process for synthesizing desoxytazobactam diphenylmethyl ester according to claim 7, wherein the ratio of 2 β -chloromethyl penicillanic acid diphenylmethyl ester: triazole: acetone: water 1 (0.3-0.7), (0.5-0.7), (0.15-0.25); the dosage of the catalyst is 0.5 to 1 percent of the weight of the 2 beta-chloromethyl penicillanic acid diphenylmethyl ester.
9. The method for synthesizing desoxytazobactam diphenylmethyl ester as claimed in claim 7, wherein the acetone and n-hexane are recrystallized to: firstly adding acetone for dissolving, then dropwise adding n-hexane until solid is separated out, and then stirring at room temperature for 0.5-1 h; and cooling to-5-0 ℃ for crystallization for 2-3 h, carrying out suction filtration, washing the precipitated solid, and drying to obtain the desoxytazobactam diphenylmethyl ester.
10. The method for synthesizing desoxytazobactam diphenylmethyl ester as claimed in claim 9, wherein the volume ratio of the acetone to the n-hexane is 1: 0.1-0.2.
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| TANMOY MAITY等: ""A post-synthetically modified metal–organic framework for copper catalyzed denitrative C–N coupling of nitroarenes under heterogeneous conditions"", 《NEW J. CHEM》, vol. 45, pages 5568 * |
| 邓勇等: ""β-内酰胺酶抑制剂——他唑巴坦酸的合成"", 《中国药物化学杂志》, vol. 11, no. 2, pages 93 - 95 * |
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