Synthetic method of avibactam sodium

Abstract

The invention discloses a synthesis method of avibactam sodium in the technical field of medical chemical synthesis. The avibactam sodium is obtained by taking L-pyroglutamic acid as a starting raw material through propenyl protection, t-butyloxycarboryl protection, sulfur ylide ring opening, chlorination to form oxime, t-butyloxycarboryl removal, ring closing, chiral carbon construction, isomer resolution, ammonolysis, urea ring generation through condensation, catalytic debenzylation, sulfonation and ion exchange. In order to solve the problem that reagents used in the carboxyl protection process are dangerous, allyl alcohol is used for replacing benzyl chloride to serve as a carboxyl protective agent, meanwhile, a nano-palladium catalyst is prepared to be used for removing protective groups, and cost reduction and reaction rate improvement are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a method for synthesizing avibactam sodium. Background Art

[0002] Antibiotics are drugs used to treat bacterial infections. They are generally produced by the metabolism of microorganisms or higher animals and plants. They can inhibit the growth of bacteria or directly kill bacteria, making many infections that were originally fatal treatable. Avibactam sodium is a new type of β-lactamase inhibitor that does not contain a β-lactam ring structure. Its chemical name is [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl] sodium sulfate. The current synthesis methods can be divided into three categories: L- Avibactam sodium is synthesized using pyroglutamic acid derivatives as starting materials, chiral piperidine ring derivatives as starting materials, and olefin derivatives as starting materials; among them, L-pyroglutamic acid derivatives as starting materials have low costs, but low yields and use a large amount of toxic reagents; chiral piperidine ring derivatives as starting materials are difficult to synthesize, the cost is very high, and the metal catalyst used is easy to remain, the yield of the target product is low; olefin derivatives as starting materials have complicated synthesis steps, extremely low yields, and are difficult to use for industrial production; The synthesis of avibactam sodium using L-pyroglutamic acid derivatives as starting materials is currently the most suitable route for industrial production, but the benzyl chloride used in the carboxyl protection process is highly dangerous, and the heavy metal catalysts used in the traditional process to remove the protecting group are inefficient and easily cause heavy metal residues. Summary of the invention

[0003] In view of the above situation, in order to overcome the defects of the prior art, the present invention provides a method for synthesizing avibactam sodium. In order to solve the problem of the danger of reagents used in the carboxyl protection process, the present invention proposes to use allyl alcohol instead of benzyl chloride as a carboxyl protecting agent, and at the same time prepare a nano palladium catalyst for the removal of the protecting group, thereby achieving cost reduction and improvement of the reaction rate.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows: The present invention proposes a method for synthesizing avibactam sodium, comprising the following steps: a. Using L-pyroglutamic acid as a starting material, protecting the carboxyl group on L-pyroglutamic acid with a carboxyl protecting agent to obtain A1, adding a tert-butyloxycarbonyl group to the pyrrole ring N of A1 to obtain A2, performing a ring-opening reaction on A2 with sulfur ylide to break the amide bond of the pyrrole ring to obtain A3, chlorinating the dimethyl sulfoxide group of A3, and reacting the carbon-oxygen bond to an oxime structure to obtain A4, removing the tert-butyloxycarbonyl group of A4 with methanesulfonic acid and catalyzing the ring-closing with potassium bicarbonate to obtain A5, reducing the carbon-nitrogen double bond of A5 to an S-configuration carbon-nitrogen bond, and salifying the product with oxalic acid through hydrogen bonding to obtain A6; b. A6 obtained in step a is subjected to aminolysis, condensation to form a urea ring, catalytic debenzylation, sulfonation, and ion exchange to obtain A10 avibactam sodium.

[0005] Preferably, in step a, the carboxyl protecting agent is allyl alcohol.

[0006] Preferably, the catalyst used for the catalytic debenzylation in step b is a nano-palladium catalyst.

[0007] Furthermore, the nano palladium catalyst is obtained by replacing part of Zn with Pd through a replacement reaction of carbonized ZIF-8.

[0008] The preparation method of the nano palladium catalyst comprises the following steps: S1, dissolving zinc nitrate hexahydrate in methanol to obtain a zinc nitrate solution, dissolving 2-methylimidazole in methanol to obtain a 2-methylimidazole solution, and dissolving palladium nitrate dihydrate in water to obtain a palladium nitrate solution; S2, adding the 2-methylimidazole solution obtained in S1 to the zinc nitrate solution obtained in S1, stirring at 200 rpm in a water bath at 36°C for 4 h, filtering and drying to obtain ZIF-8; S3. The ZIF-8 obtained in S2 is calcined at 800° C. for 2 h under argon protection, and then added to the palladium nitrate solution obtained in S1 after cooling, and immersed for 8 h, filtered, and dried to obtain C-Zn / Pd, i.e., nano-palladium catalyst.

[0009] Preferably, in S1, the zinc nitrate solution Zn 2+ The molar ratio with 2-methylimidazole is 1:7-8; Preferably, in S1, palladium nitrate solution Pb 2+ With zinc nitrate solution Zn 2+ The molar ratio is 1:0.6-0.8.

[0010] The beneficial effects achieved by the present invention are as follows: allyl alcohol is used as a carboxylic acid protective agent, which has low toxicity, is safe and stable, is easy to remove, and is conducive to safe production and improved yield; ZIF-8 is synthesized by using zinc nitrate and 2-methylimidazole, and Zn is reduced while forming a carbon skeleton during high-temperature calcination in an argon atmosphere, and part of Zn is converted into Pd by replacement, and the unique structure of the formed C skeleton can fix metal particles and avoid agglomeration of palladium particles, increase surface active sites, and the synergistic effect of the introduced Zn and Pd can accelerate the electron transfer rate and promote the adsorption and storage of H, thereby improving the reaction rate and catalytic performance. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 This is a flow chart of preparing avibactam sodium according to Example 1 of the present invention; Figure 2 The total yields of Examples 1-3 and Comparative Examples 1-3 of the present invention are shown in FIG. Figure 3 It is a result diagram of the cycle test of Examples 1-3 and Comparative Example 2 of the present invention.

[0012] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention. DETAILED DESCRIPTION

[0013] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0014] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0015] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials used in the following examples are purchased from commercial channels unless otherwise specified.

[0016] Example 1

[0017] Figure 1This is a flow chart of preparing avibactam sodium in Example 1 of the present invention; as shown in the figure, avibactam sodium is prepared from L-pyroglutamic acid as a starting material through propylene protection, tert-butyloxycarbonyl protection, sulfur ylide ring opening, chlorination to form oxime, de-tert-butyloxycarbonylation, ring closing, construction of chiral carbon, isomer resolution, aminolysis, condensation to form urea ring, catalytic debenzylation, sulfonation, and ion exchange; The synthesis method of avibactam sodium specifically comprises the following steps: (1) Synthesis of intermediate product A2 Take 0.1 mol of L-pyroglutamic acid (L-Pyr), i.e. A0, and add it to a reaction container. Then add 0.1 mol of allyl alcohol, 0.1 mol of N,N'-dicyclohexylcarbodiimide (DCC), 0.08 mol of 4-dimethylaminopyridine (DMAP), and 200 mL of dichloromethane solution (DCM). Stir at -3°C for 2 h, and heat to 25°C for reaction. The raw material spot almost disappears as detected by thin layer chromatography (TLC). Filter to obtain intermediate product A1 liquid. Add 14 mL of liquid triethylamine (NEt3). Dissolve 1.2 mol of di-tert-butyl coke (Boc2O) in 30 mL of DCM and slowly dropwise add at 0°C. React at room temperature until the relative content of the raw material is less than 0.25%. Wash with 1 mol / L dilute hydrochloric acid, remove DCM by vacuum distillation, add 6 mL of ethyl acetate (EtOAc) and 45 mL of n-hexane, crystallize at 3°C, filter, wash, and dry to obtain a white powder, i.e., intermediate product A2. (2) Synthesis of intermediate product A3 Take 0.1 mol of the intermediate product A2 obtained in step (1) and dissolve it in 65 mL of tetrahydrofuran to obtain A2 solution. Add 1.1 mol of potassium tert-butoxide (KO t Bu) was added to 120 mL of DMSO at 25 °C to fully dissolve, and 90 mL of tetrahydrofuran and 1.25 mol of trimethylsulfoxide iodide ((CH3)3S + OI - ), heat to 25°C, stir for 1h, cool to -12°C, add A2 solution, heat to -5°C, stir and react until the raw material spot disappears by TLC detection, cool to -12°C, add 20% ammonium chloride solution, remove tetrahydrofuran by vacuum distillation, add 200mL ethyl acetate to extract once, add 100mL ethyl acetate to extract twice, combine, wash, and vacuum distill to obtain intermediate product A3 liquid; (3) Synthesis of intermediate product A4 Add 50 mL of ethyl acetate to the intermediate product A3 solution obtained in step (2), add 0.1 mol of O-benzylhydroxylamine hydrochloride (BnONH2·HCl), reflux at 60°C until the half point of the raw material disappears as detected by TLC, wash with 20% NaCl solution, separate the liquids, and collect the organic phase to obtain the intermediate product A4 solution; (4) Synthesis of intermediate product A5 19.6 mL of methanesulfonic acid (MeSO3H) was added dropwise to the intermediate product A4 solution obtained in step (3). After the addition was completed, the mixture was heated to an external temperature of 45°C, and a 15% aqueous sodium bicarbonate solution (KHCO3) was added dropwise. The mixture was stirred vigorously for 1.5 h. The organic phase was washed with 20% sodium chloride, separated, and the organic phase was collected to obtain the intermediate product A5 solution. (5) Synthesis of intermediate product A6 0.2 mol of sodium borohydride (NaBH4) was added to 150 mL of ethyl acetate, and the mixture was stirred at low temperature to be uniformly mixed. 45 mL of propionic acid was slowly added dropwise. After the addition was completed, the mixture was stirred for 6 h to obtain a reaction solution. The intermediate product A5 obtained in step (4) was cooled to -30°C, 27.5 mL of 98% concentrated sulfuric acid (H2SO4) was added dropwise, and the mixture was kept at -25°C and stirred uniformly. The reaction solution was added dropwise, and the mixture was stirred at -20°C for 30 min. Water was added to quench the reaction, and the pH was adjusted to 8. The mixture was heated to 40°C, allowed to stand, separated, and the organic phase was washed. 130 mL of 9.2% isopropanol (IPA) solution of dihydrate oxalic acid ((COOH)2·2H2O) was added dropwise. 130 mL of anhydrous methanol (MeOH) was added, the mixture was heated to 45°C and stirred for 1 h. The mixture was cooled, filtered, washed, and dried to obtain the intermediate product A6. (6) Synthesis of intermediate product A7 The intermediate product A6 obtained in step (5) was transferred to an autoclave, 7M ammonia methanol was added, and the reaction was stirred in a sealed manner at 25°C until the raw material spot disappeared under TLC detection, 500mL of methyl tert-butyl ether was added, and the reaction was stirred at high speed for 1h, and the intermediate product A7 was obtained by suction filtration, washing, and drying; (7) Synthesis of intermediate product A8 The intermediate product A7 obtained in step (6) was added to 350 mL of acetonitrile (AN), maintained at a constant temperature of 6°C, 100 mL of N,N-diisopropylethylamine (DIPEA) was added, 30 mL of dichlorodimethylsilane (Me2SiCl2) was added dropwise, and stirred for 1 h until the solution was clear, 1.3 mol of N,N-carbonyldiimidazole (CDI) was added, the temperature was raised to 45°C and stirred for 3 h, 50 mL of isopropanol was added, and stirring was continued for 4 h, and 350 mL of dichloromethane was added to cool, and the mixture was washed with 2 mol / L dilute hydrochloric acid. The dichloromethane phase was separated and concentrated, crystallized, filtered, washed, and dried to obtain the intermediate product A8; (8) Synthesis of intermediate product A9 The intermediate product A8 obtained in step (7) is added to 40 mL of isopropanol, 40 mL of deionized water, 6% nano-palladium catalyst (C-Zn / Pd) of the intermediate product A7 by mass, 1.2 mol of trimethylamine sulfur trioxide (SO3-NMe3) and 1 mL of triethylamine are added, hydrogen (H2) is introduced and reacted for 6 h until the raw material point disappears, diatomaceous earth is filtered to remove the C-Zn / Pd catalyst, butyl acetate is added to the filtrate to remove toluene, 30 mL of isopropanol solution of tetra-n-octylammonium bromide (TOAB) with a concentration of 6.2% isopropanol is taken from the aqueous phase, stirred at 45°C for 5 h, cooled and extracted, 15 mL of isopropanol solution of tetra-n-octylammonium bromide with a concentration of 2.4% isopropanol is added, stirred at 45°C for 3 h, cooled to room temperature, extracted with dichloromethane, and concentrated to obtain a feed liquid of the intermediate product A9; (9) Synthetic product A10 The intermediate product A9 obtained in step (8) was added to 30 mL of anhydrous ethanol, 0.2 mol of sodium-2-ethylhexanoate was added to the anhydrous ethanol, and the mixture was added dropwise to the reaction system. The mixture was stirred for reaction for 5 h, filtered, rinsed, added to anhydrous ethanol, stirred at 25 °C for 2 h, filtered, and dried to obtain the product A10, i.e., avibactam sodium.

[0018] The preparation method of nano palladium catalyst comprises the following steps: S1, dissolving 2.2 g of zinc nitrate hexahydrate in 100 mL of methanol to obtain a zinc nitrate solution, dissolving 4.86 g of 2-methylimidazole in 100 mL of methanol to obtain a 2-methylimidazole solution, and dissolving 1.98 g of palladium nitrate dihydrate in water to obtain a palladium nitrate solution; S2, adding the 2-methylimidazole solution obtained in S1 to the zinc nitrate solution obtained in S1, stirring at 200 rpm in a water bath at 36°C for 4 h, filtering and drying to obtain ZIF-8; S3. The ZIF-8 obtained in S1 is calcined at 800° C. for 2 h under argon protection, cooled, added to the palladium nitrate solution obtained in S1, immersed for 8 h, filtered, and dried to obtain C-Zn / Pd, i.e., nano-palladium catalyst.

[0019] Example 2

[0020] Compared with Example 1, the preparation method of the nano palladium catalyst comprises the following steps: S1, dissolving 2.2 g of zinc nitrate hexahydrate in 100 mL of methanol to obtain a zinc nitrate solution, dissolving 4.26 g of 2-methylimidazole in 100 mL of methanol to obtain a 2-methylimidazole solution, and dissolving 1.74 g of palladium nitrate dihydrate in water to obtain a palladium nitrate solution; S2, adding the 2-methylimidazole solution obtained in S1 to the zinc nitrate solution obtained in S1, stirring at 200 rpm in a water bath at 36°C for 4 h, filtering and drying to obtain ZIF-8; S3. The ZIF-8 obtained in S1 is calcined at 800° C. for 2 h under argon protection, cooled, added to the palladium nitrate solution obtained in S1, immersed for 8 h, filtered, and dried to obtain C-Zn / Pd, i.e., nano-palladium catalyst.

[0021] The rest is the same as Example 1.

[0022] Example 3

[0023] The preparation method of nano palladium catalyst comprises the following steps: S1, dissolving 2.2 g of zinc nitrate hexahydrate in 100 mL of methanol to obtain a zinc nitrate solution, dissolving 4.45 g of 2-methylimidazole in 100 mL of methanol to obtain a 2-methylimidazole solution, and dissolving 1.86 g of palladium nitrate dihydrate in water to obtain a palladium nitrate solution; S2, adding the 2-methylimidazole solution obtained in S1 to the zinc nitrate solution obtained in S1, stirring at 200 rpm in a water bath at 36°C for 4 h, filtering and drying to obtain ZIF-8; S3. The ZIF-8 obtained in S1 is calcined at 800° C. for 2 h under argon protection, cooled, added to the palladium nitrate solution obtained in S1, immersed for 8 h, filtered, and dried to obtain C-Zn / Pd, i.e., nano-palladium catalyst.

[0024] The rest is the same as Example 1.

[0025] Comparative Example 1 Compared with Example 1, the carboxyl protecting agent is benzyl chloride, and the rest is the same as Example 1.

[0026] Comparative Example 2 Compared with Example 2, the catalyst used for catalytic debenzylation is commercially available palladium carbon (10%) with the product number P1504, and the rest is the same as Example 1.

[0027] Comparative Example 3 Compared with Example 1, the carboxyl protecting agent is benzyl chloride, the catalyst used for catalytic debenzylation is commercially available palladium carbon (10%) with the product number P1504, and the rest is the same as Example 1.

[0028] 1. Yield Analysis The total yields of Examples 1-3 and Comparative Examples 1-3 were calculated based on the product avibactam sodium.

[0029] Yield = production amount / theoretical production amount × 100%.

[0030] Figure 2The result diagram of the total yields of Examples 1-3 of the present invention and Comparative Examples 1-3 is shown in the figure. As shown in the figure, the total yields of Examples 1-3 are 42.3%, 41.6% and 43.5%, respectively, and the total yields of Comparative Examples 1-3 are 36.9%, 31.1% and 26.7%; the total yield of Examples 1-3 is significantly higher than that of Comparative Examples 1-3, indicating that the use of acryl alcohol instead of benzyl chloride and the use of nano palladium catalyst have an effect of improving the product yield.

[0031] 2. Cycle test When the synthetic intermediate product A9 experiment was performed once and 20 times, the yields of Examples 1-3 and Comparative Example 2 were calculated, and the yield reduction rate was calculated. Yield reduction rate = (yield of the first experiment - yield of the 20th experiment) / yield of the first experiment × 100%.

[0032] Figure 3 It is a result diagram of the cyclic test of Examples 1-3 and Comparative Example 2 of the present invention. As shown in the figure, the yield reduction rates of Examples 1-3 are 12.6%, 13.5%, and 12.1%, respectively, and the yield reduction rate of Comparative Example 2 is 51.6%; the yield reduction rate of Examples 1-3 is significantly lower than that of Comparative Example 2, indicating that the prepared nano palladium catalyst is more stable than commercially available palladium carbon and can be reused.

[0033] While the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that many changes, modifications, substitutions and variations can be made to the embodiments without departing from the principles and spirit of the invention.

[0034] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing avibactam sodium, characterized in that: The steps include: a. Using L-pyroglutamic acid as a starting material, protecting the carboxyl group on L-pyroglutamic acid with a carboxyl protecting agent to obtain A1, adding a tert-butyloxycarbonyl group to the pyrrole ring N of A1 to obtain A2, performing a ring-opening reaction on A2 with a sulfur ylide to break the amide bond of the pyrrole ring to obtain A3, chlorinating the dimethyl sulfoxide group of A3, and reacting the carbon-oxygen bond to an oxime structure to obtain A4, removing the tert-butyloxycarbonyl group of A4 with methanesulfonic acid and catalyzing the ring-closing with potassium bicarbonate to obtain A5, reducing the carbon-nitrogen double bond of A5 to an S-configuration carbon-nitrogen bond, and salifying the product with oxalic acid through hydrogen bonding to obtain A6; b. A6 obtained in step a is subjected to aminolysis, condensation to form a urea ring, catalytic debenzylation, sulfonation, and ion exchange to obtain A10 avibactam sodium.

2. The method for synthesizing avibactam sodium according to claim 1, wherein: In step a, the carboxyl protecting agent is allyl alcohol.

3. The method for synthesizing avibactam sodium according to claim 2, wherein: In step b, the catalyst used for the catalytic debenzylation is a nano-palladium catalyst.

4. The method for synthesizing avibactam sodium according to claim 3, wherein: The nano palladium catalyst is obtained by replacing part of Zn with Pd through a replacement reaction of carbonized ZIF-8. The preparation method thereof comprises the following steps: S1, dissolving zinc nitrate hexahydrate in methanol to obtain a zinc nitrate solution, dissolving 2-methylimidazole in methanol to obtain a 2-methylimidazole solution, and dissolving palladium nitrate dihydrate in water to obtain a palladium nitrate solution; S2, adding the 2-methylimidazole solution obtained in S1 to the zinc nitrate solution obtained in S1, stirring at 200 rpm in a water bath at 36°C for 4 h, filtering and drying to obtain ZIF-8; S3. The ZIF-8 obtained in S2 is calcined at 800° C. for 2 h under argon protection, cooled, added to the palladium nitrate solution obtained in S1, immersed for 8 h, filtered, and dried to obtain C-Zn / Pd, i.e., nano-palladium catalyst.

5. The method for synthesizing avibactam sodium according to claim 4, wherein: In S1, zinc nitrate solution Zn 2+ The molar ratio of palladium nitrate solution Pb 2+ With zinc nitrate solution Zn 2+ The molar ratio is 1:0.6-0.8.

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