CN115073458A - Preparation method of avibactam sodium - Google Patents
Preparation method of avibactam sodium Download PDFInfo
- Publication number
- CN115073458A CN115073458A CN202210777931.7A CN202210777931A CN115073458A CN 115073458 A CN115073458 A CN 115073458A CN 202210777931 A CN202210777931 A CN 202210777931A CN 115073458 A CN115073458 A CN 115073458A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- stirring
- temperature
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of avibactam sodium. The invention takes 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester as a raw material to prepare the avibactam sodium. The raw material is adopted for preparing the abamectin sodium, the hydrogenation debenzylation reaction is not needed, the hydrogenation catalytic operation in the production process is avoided, and the reaction condition is milder; meanwhile, the production route can be shortened, the stability of the preparation process is improved, and the method is more suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of avibactam sodium.
Background
Abamebactam sodium is a beta-lactamase inhibitor depending on serine, and can be connected with the hydroxyl of the serine of the enzyme through hydrolytic cleavage of self amido bond, so that the activity of the enzyme is lost. Therefore, the abamectin sodium has broad-spectrum antibacterial activity when being combined with various cephalosporin and carbapenem antibiotics, and particularly has remarkable activity on escherichia coli containing the ultra-broad-spectrum beta-lactamase, klebsiella pneumoniae, escherichia coli containing the excess AmpC enzyme and escherichia coli containing both the AmpC and the ultra-broad-spectrum beta-lactamase. It can effectively inhibit the activity of Ser-dependent enzymes in class A and class C.
The chemical name of the avibactam sodium is as follows: [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1]]Octane-6-yl]Sodium sulfate, molecular formula: c 14 H 17 N 3 O 3 Molecular weight: 287.23, CAS number: 1192491-61-4, the structural formula is as follows.
The existing literature and patent reports on the synthesis of avibactam sodium mainly include the following.
The method comprises the following steps: one synthetic route disclosed in patent WO2012086241 is as follows:
the synthesis method comprises the following steps of taking (S) -1- (benzyloxycarbonyl) -5-oxopyrrolidine-2-carboxylic acid as an initial raw material, and carrying out electrophilic addition, nucleophilic substitution, cyclization, reduction, Cbz removal, acylation protection, nucleophilic substitution, deprotection, intramolecular urethanization, hydrolysis to form salt, acidification, esterification, ammonolysis, debenzylation, sulfonic esterification, salt formation and cation exchange reaction for 15 steps to obtain the avibactam sodium. The synthesis route has more steps, part of reaction operations are complicated, the reaction time is long, the preparation of the intermediate in each step needs to be separated by a silica gel column, the total yield is low, and the industrial production is difficult to realize.
The second method comprises the following steps:
another synthesis method of avibactam sodium is disclosed in patent W02012172368, and the synthesis route is as follows:
the method takes N-Boc-L-pyroglutamic acid ethyl ester (or benzyl ester) as an initial raw material, and the avibactam sodium is obtained through 13 steps of reaction including ring opening, nucleophilic substitution, Boc removal, cyclization, reduction, ammonolysis, intramolecular urethanization, debenzylation, sulfoacid esterification, salification and cation exchange; the selectivity is low when the intermediate is reduced; resulting in a decrease in yield; meanwhile, the toxicity of the by-product generated in the reaction is high; the environmental unfriendliness and the like also limit the large-scale production.
The third method comprises the following steps:
in patent US2012032301, a third synthesis method of avibactam sodium and derivatives thereof is disclosed, and the synthesis route is as follows:
the route also takes N-Boc-L-pyroglutamic acid ethyl ester as a raw material, and the avibactam sodium is finally obtained through 13 steps of activation ring opening, ring closing and ketone forming, reduction, nucleophilic substitution, twice deprotection, ammonolysis, intramolecular carbamidation, debenzylation, sulfonic acid esterification, salification and ion exchange.
The method four comprises the following steps:
xiong et al report a process for the construction of a piperidine ring followed by the synthesis of a urea ring by olefin metathesis. The diazabicyclooctane skeleton is constructed by taking an olefin derivative as a starting material:
in the method, the reaction processes of benzyloxyamino protection and subsequent deprotection commonly exist in the preparation process; the deprotection method usually adopts a hydrogenation debenzylation reaction, so that the process risk is high, and the reaction steps are long; meanwhile, the reaction steps are long, the atom economy is poor, and the raw material cost is high.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to reduce the hydrogenation process in the production process and shorten the process steps by replacing the initial raw materials, so that the process is simpler and more feasible and has higher safety. The yield and the purity of the intermediate of the abamectin sodium are improved, and the method is more favorable for industrial production.
The technical scheme adopted by the invention for realizing the purpose is as follows:
the invention provides a preparation method of abamectin sodium, which comprises the following steps:
(1) weighing a compound IV and an ammonia solution, adding the compound IV and the ammonia solution into a three-necked bottle, stirring for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate to be dry, washing the filtrate with an organic solvent, and drying the filtrate to obtain a compound III;
(2) weighing a compound III and an organic solvent I, stirring, controlling the temperature to be 5-10 ℃, adding N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding chlorosilane, after dropwise adding, heating to be 5-10 ℃, and continuing to control the temperature to react;
(3) after the reaction is finished, adding N, N-carbonyl diimidazole into the reaction system, carrying out heat preservation reaction, after the reaction is finished, adding isopropanol, and continuing temperature control reaction;
(4) controlling the temperature to be 20-30 ℃, directly adding a sulfonation reagent, dropwise adding acid to adjust the pH value, and stirring for reaction after dropwise adding is finished;
(5) then adding 45% tetrabutylammonium salt solution, stirring, adding an extracting agent respectively, extracting twice, mixing the extracted solutions after extraction, and concentrating to dryness. Then adding an organic solvent II, stirring for crystallization, transferring into a cold bath, cooling for crystallization, performing suction filtration, and washing. Carrying out suction filtration and drying a filter cake; obtaining a compound II;
(6) adding the compound II, the organic solvent III and the purified water into a reaction bottle, stirring and dissolving to obtain a compound II solution, adding the sodium isooctanoate and the organic solvent III into another reaction bottle, and stirring and dissolving to obtain a sodium isooctanoate solution;
slowly dripping the sodium isooctanoate solution into the compound II solution, stirring for reaction after dripping, filtering, washing a filter cake, and drying to obtain the compound I avibactam sodium.
Further, in the step (1), the compound IV is 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester or oxalate or other salts, preferably 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate.
Further, in the step (1), the ammonia solution is a mixed solution of methanol, ethanol, isopropanol, n-propanol or a mixture thereof and ammonia gas; the concentration of the ammonia gas is 7-9 mol/L; the mol ratio of the ammonia to the compound IV is 28-40: 1, preferably 28-36: 1; the organic solvent is one or a mixture of more of ethyl acetate, butyl acetate, ethyl formate or methyl tert-butyl ether, and ethyl acetate is preferred.
Further, in the step (2), the organic solvent I is one or a mixture of acetonitrile, phenylacetonitrile or propionitrile, preferably acetonitrile; the chlorosilane is dichlorodimethylsilane, dichlorodiphenylsilane, trichloromethylsilane, trichlorophenylsilane or a mixture of one or more of dichlorodimethylsilane, dichlorodiphenylsilane and trichlorophenylsilane, preferably dichlorodimethylsilane; the molar ratio of the chlorosilane to the compound III is 1.20-3.0: 1, preferably 1.20-2.0: 1; the temperature control reaction time is 1-2 h.
Further, in the step (2), the molar ratio of the N, N-diisopropylethylamine to the compound III is 1.05-2.0: 1, preferably 1.07-1.2: 1.
Further, in the step (3), the molar ratio of the N, N-carbonyldiimidazole to the compound III is 1.1-2.0: 1, preferably 1.1-1.5: 1; the temperature of the heat preservation reaction is 30-35 ℃, the reaction time is 8-15 h, and 8-10 h is preferred; the molar ratio of the isopropanol to the compound III is 3.0-8.0: 1, preferably 4.0-5.0: 1; after the isopropanol is added, the temperature of the temperature-controlled reaction is 30-35 ℃, and the reaction time is 4.0-5.0 h.
Further, in the step (4), the sulfonation reagent is sulfur trioxide trimethylamine, sulfur trioxide pyridine, N-ethyldiisopropylamine sulfur trioxide complex or sulfur trioxide triethylamine, preferably sulfur trioxide trimethylamine; the molar ratio of the sulfonation reagent to the compound III is 1.0-2.0: 1; the acid is hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof, preferably hydrochloric acid; dropwise adding acid to adjust the pH value to 3-4; the reaction time after the pH is adjusted is 4-6 h;
further, in the step (5), the tetrabutylammonium salt solution is tetrabutylammonium acetate, tetrabutylammonium bromide, tetrabutylammonium oxalate, tetrabutylammonium hydroxide, tetrabutylammonium sulfate or one or more mixtures thereof, preferably tetrabutylammonium acetate; the molar ratio of the tetrabutylammonium salt to the compound III is 1.0-2.0: 1, preferably 1.0-1.5: 1; the extractant is dichloromethane, trichloromethane or ethyl acetate, preferably dichloromethane; the organic solvent II is 4-methyl-2-pentanone or ethyl acetate, preferably 4-methyl-2-pentanone; the mass ratio of the organic solvent II to the compound III is 4-7: 1, preferably 4-5: 1; the temperature of the crystallization is-5 to 5 ℃, and the time is 1 to 2 hours.
Further, in the step (6), the organic solvent III is ethanol, methanol, isopropanol, n-propanol or a mixture of several of them, preferably ethanol; the molar ratio of the sodium isooctanoate to the compound II is 1.5-3.0: 1, preferably 2.0-2.5: 1; the dropping time of the sodium isooctanoate solution is 2-5 h, preferably 3-4 h; the reaction time is 2-4 h.
The synthetic route of the invention is as follows:
the invention has the beneficial effects that:
(1) the invention provides a preparation method of avibactam sodium, which uses a compound IV as a raw material to prepare the avibactam sodium. The method avoids using a hydrogenation debenzylation reaction, reduces reaction steps and simplifies the operation of the reaction process.
(2) The preparation method provided by the invention has higher process safety and is more suitable for industrial production; meanwhile, the yield and the purity of the product are also improved.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Example 1
(1) Preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxamide
Weighing 41g (0.119 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate and 300g of ammonia methanol, adding into a three-necked bottle, stirring for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate to dryness, washing with 70g of ethyl acetate, drying and drying. 24.2g of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide is obtained with a yield of 90.0%. .
(2) Preparation of tetrabutyl ammonium salt ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl)
Adding 200ml of acetonitrile into a flask, adding 20.80g (0.080 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide, stirring, controlling the temperature to be 5-10 ℃, then adding 11.09g (0.086 mol) of N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding 12.38g (0.096 mol) of dichlorodimethylsilane, heating to be 5-10 ℃ after the dropwise adding is finished, stirring for 1H, after the reaction is finished, adding 15.89g (0.098 mol) of N, N-carbonyldiimidazole into the reaction system, controlling the temperature to be 30-35 ℃, and continuing to react for 10H; after the reaction is finished, 20g (0.32 mol) of isopropanol is added, the temperature is continuously controlled to be 30-35 ℃, and the stirring reaction is carried out for 4 hours.
And (3) controlling the temperature to be 20-30 ℃ after the reaction is finished, adding 11.1g (0.080 mol) of sulfur trioxide trimethylamine complex, controlling the temperature to be 20-30 ℃, and dropwise adding hydrochloric acid to adjust the pH value to be about 4. After the completion of the dropwise addition, stirring was carried out for 5 hours until the reaction was completed. And then adding 67.25g of 45% tetrabutylammonium acetate solution (containing 0.1mol of tetrabutylammonium acetate), stirring for 10min, respectively adding 150g of dichloromethane and 80g of dichloromethane for extraction, mixing the extracted solutions after extraction, concentrating to dryness, then adding 97.8g of 4-methyl-2-pentanone, stirring for crystallization, transferring into a cold bath, cooling to-5 ℃, crystallizing for 1-2 h, performing suction filtration, and washing by using cold 4-methyl-2-pentanone. And (5) pumping and drying. 24.9g of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was obtained in a yield of 61.5%.
(3) Preparation of avibactam sodium
20g (0.039 mol) of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was charged into a reaction flask, and then 90g of anhydrous ethanol and 5g of purified water were added thereto and dissolved with stirring.
13.4g (0.08 mol) of sodium isooctanoate and 107.5g of absolute ethyl alcohol were added to another bottle and dissolved by stirring to prepare a solution. Then, the sodium isooctanoate solution was slowly dropped into the reaction solution of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt, and after dropping for about 3 hours, a white solid was precipitated, followed by stirring for 2 hours, suction filtration, and washing of the cake with absolute ethanol. 10.45g of abamectin sodium is obtained, and the yield is 92.2%. The purity of the related substances is 99.69 percent.
Example 2
(1) Preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxamide
41g (0.119 mol) of ethyl 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylate oxalate and 300g of ammonia methanol are weighed and added into a three-necked bottle, stirred for reaction, filtered after the reaction is finished, concentrated to be dry, and washed by 70g of ethyl acetate. To obtain 24.2g of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide. The yield thereof was found to be 90.0%.
(2) Preparation of tetrabutyl ammonium salt ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl)
Adding 200ml of acetonitrile into a flask, adding 20.80g (0.080 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide, controlling the temperature to be 5-10 ℃, stirring, then adding 11.09g (0.086 mol) of N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding 15.48g (0.12 mol) of dichlorodimethylsilane, after the dropwise adding is finished, heating to be 5-10 ℃, stirring for 1H, after the reaction is finished, adding 15.89g (0.098 mol) of N, N-carbonyldiimidazole into the reaction system, controlling the temperature to be 30-35 ℃, and continuing to react for 9H; after the reaction is finished, 20g (0.32 mol) of isopropanol is added, the temperature is continuously controlled to be 30-35 ℃, and the stirring reaction is carried out for 4 hours.
And (3) controlling the temperature to be 20-30 ℃ after the reaction is finished, adding 11.1g (0.080 mol) of sulfur trioxide trimethylamine complex, controlling the temperature to be 20-30 ℃, and dropwise adding hydrochloric acid to adjust the pH value to be about 4. After the completion of the dropwise addition, stirring was carried out for 5 hours until the reaction was completed. And then adding 67.25g of 45% tetrabutylammonium acetate solution (containing 0.1mol of tetrabutylammonium acetate), stirring for 10min, respectively adding 150g of dichloromethane and 80g of dichloromethane for extraction, mixing the extracted solutions after extraction, concentrating to dryness, then adding 98.0g of 4-methyl-2-pentanone, stirring for crystallization, transferring into a cold bath, cooling to-5 ℃, crystallizing for 1-2 h, performing suction filtration, and washing by using cold 4-methyl-2-pentanone. And (5) pumping and drying. 27.1g of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was obtained in a yield of 67.1%.
(3) Preparation of avibactam sodium
20g (0.039 mol) of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was charged into a reaction flask, and then 90g of anhydrous ethanol and 5g of purified water were added thereto and dissolved with stirring.
13.4g (0.08 mol) of sodium isooctanoate and 107.5g of absolute ethyl alcohol were added to another bottle and dissolved by stirring to prepare a solution. And slowly dripping sodium isooctanoate solution into the reaction solution for 4 hours, separating out white solid, stirring for 2 hours, carrying out suction filtration, and washing a filter cake by using absolute ethyl alcohol. 10.23g of abamectin sodium is obtained, and the yield is 90.3%. The purity of the related substances is 99.75 percent.
Example 3
(1) Preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxamide
41g (0.119 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate and 385g of ammonia methanol are weighed and added into a 500ml three-necked bottle, stirred for reaction, filtered after the reaction is finished, the filtrate is concentrated to be dry, and 70g of ethyl acetate is washed. To obtain 25.1g of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide with the yield of 93.3 percent.
(2) Preparation of tetrabutyl ammonium salt ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl)
Adding 200ml of acetonitrile into a flask, adding 20.80g (0.080 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide, controlling the temperature to be 5-10 ℃, stirring, then adding 11.09g (0.086 mol) of N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding 12.38g (0.096 mol) of dichlorodimethylsilane, after the dropwise adding is finished, heating to be 5-10 ℃, stirring for 1.5H, after the reaction is finished, adding 25.9g (0.160 mol) of N, N-carbonyldiimidazole into the reaction system, controlling the temperature to be 30-35 ℃, and continuing to react for 8H; after the reaction is finished, 20g (0.32 mol) of isopropanol is added, the temperature is continuously controlled to be 30-35 ℃, and the stirring reaction is carried out for 4 hours.
And (3) controlling the temperature to be 20-30 ℃ after the reaction is finished, adding 13.9g (0.10 mol) of sulfur trioxide trimethylamine complex, controlling the temperature to be 20-30 ℃, and dropwise adding hydrochloric acid to adjust the pH value to be about 4. After the addition was complete, the mixture was stirred for 4.5h until the reaction was complete. And then adding 67.25g of 45% tetrabutylammonium acetate solution (containing 0.1mol of tetrabutylammonium acetate), stirring for 10min, respectively adding 150g of dichloromethane and 80g of dichloromethane for extraction, mixing the extracted solutions after extraction, concentrating to dryness, then adding 98.0g of 4-methyl-2-pentanone, stirring for crystallization, transferring into a cold bath, cooling to-5 ℃, crystallizing for 1-2 h, performing suction filtration, and washing by using cold 4-methyl-2-pentanone. And (5) pumping and drying. 27.46g of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was obtained in a yield of 68.0%.
(3) Preparation of avibactam sodium
20g (0.039 mol) of tetrabutylammonium ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) salt was charged into a reaction vessel, and then 90g of anhydrous ethanol and 5g of purified water were added thereto and dissolved with stirring.
16.75g (0.08 mol) of sodium isooctanoate and 107.5g of absolute ethyl alcohol were added to another bottle, and dissolved by stirring to prepare a solution. And slowly dripping sodium isooctanoate solution into the reaction solution for 4 hours, separating out white solid, stirring for 2 hours, carrying out suction filtration, and washing a filter cake by using absolute ethyl alcohol. 10.38g of abamectin sodium is obtained, and the yield is 91.6%. The purity of the related substances is 99.72 percent.
Example 4
(1) Preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxamide
41g (0.119 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate and 330g of ammonia methanol are weighed and added into a 500ml three-necked bottle, stirred for reaction, filtered after the reaction is finished, the filtrate is concentrated to be dry, and 70g of ethyl acetate is washed. 24.24g of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide is obtained with a yield of 90.1%.
(2) Preparation of tetrabutyl ammonium salt ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl)
Adding 200ml of acetonitrile into a flask, adding 20.80g (0.080 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide, controlling the temperature to be 5-10 ℃, stirring, then adding 12.38g (0.096 mol) of N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding 12.38g (0.096 mol) of dichlorodimethylsilane, after the dropwise adding is finished, heating to be 5-10 ℃, stirring for 1.5H, after the reaction is finished, adding 15.89g (0.098 mol) of N, N-carbonyldiimidazole into the reaction system, controlling the temperature to be 30-35 ℃, and continuing to react for 8H; after the reaction is finished, 20g (0.32 mol) of isopropanol is added, the temperature is continuously controlled to be 30-35 ℃, and the stirring reaction is carried out for 5 hours.
And (3) controlling the temperature to be 20-30 ℃ after the reaction is finished, adding 13.9g (0.10 mol) of sulfur trioxide trimethylamine complex, controlling the temperature to be 20-30 ℃, and dropwise adding hydrochloric acid to adjust the pH value to be about 4. After the completion of the dropwise addition, stirring was carried out for 6 hours until the reaction was completed. And then adding 67.25g of 45% tetrabutylammonium acetate solution (containing 0.1mol of tetrabutylammonium acetate), stirring for 10min, respectively adding 150g of dichloromethane and 80g of dichloromethane for extraction, mixing the extracted solutions after extraction, concentrating to dryness, then adding 98.0g of 4-methyl-2-pentanone, stirring for crystallization, transferring into a cold bath, cooling to-5 ℃, crystallizing for 1-2 h, performing suction filtration, and washing by using cold 4-methyl-2-pentanone. And (5) pumping and drying. 27.30g of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutyl ammonium salt was obtained in a yield of 67.6%.
(3) Preparation of avibactam sodium
20g (0.039 mol) of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was charged into a reaction flask, and then 90g of anhydrous ethanol and 5g of purified water were added thereto and dissolved with stirring.
15.0g (0.09 mol) of sodium isooctanoate and 107.5g of absolute ethanol were added to another bottle and dissolved by stirring to prepare a solution. And slowly dripping sodium isooctanoate solution into the reaction solution for 4 hours, separating out white solid, stirring for 2 hours, carrying out suction filtration, and washing a filter cake by using absolute ethyl alcohol. 10.50g of abamectin sodium is obtained, and the yield is 92.7%. The purity of the related substances is 99.80 percent.
Comparative example 1
(1) Preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxamide
41g (0.119 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate and 250g of ammonia methanol are weighed and added into a 500ml three-necked bottle, stirred for reaction, filtered after the reaction is finished, the filtrate is concentrated to be dry, and 70g of ethyl acetate is washed. To obtain 21.7g of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide with the yield of 80.7 percent.
(2) Preparation of tetrabutyl ammonium salt { [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl)
Adding 200ml of acetonitrile into a flask, adding 20.80g (0.080 mol) of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-formamide, controlling the temperature to be 5-10 ℃, stirring, then adding 11.09g (0.086 mol) of N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding 10.31g (0.08 mol) of dichlorodimethylsilane, after the dropwise adding is finished, heating to be 5-10 ℃, stirring for 1.5H, after the reaction is finished, adding 25.9g (0.160 mol) of N, N-carbonyldiimidazole into the reaction system, controlling the temperature to be 30-35 ℃, and continuing to react for 8H; after the reaction is finished, 20g (0.32 mol) of isopropanol is added, the temperature is continuously controlled to be 30-35 ℃, and the stirring reaction is carried out for 4 hours.
And (3) controlling the temperature to be 20-30 ℃ after the reaction is finished, adding 13.9g (0.10 mol) of sulfur trioxide trimethylamine complex, controlling the temperature to be 20-30 ℃, and dropwise adding hydrochloric acid to adjust the pH value to be about 4. After the addition was complete, the mixture was stirred for 4.5h until the reaction was complete. And then adding 67.25g of 45% tetrabutylammonium acetate solution (containing 0.1mol of tetrabutylammonium acetate), stirring for 10min, respectively adding 150g of dichloromethane and 80g of dichloromethane for extraction, mixing the extracted solutions after extraction, concentrating to dryness, then adding 98.0g of 4-methyl-2-pentanone, stirring for crystallization, transferring into a cold bath, cooling to-5 ℃, crystallizing for 1-2 h, performing suction filtration, and washing by using cold 4-methyl-2-pentanone. And (5) pumping and drying. 24.23g of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was obtained in a yield of 60.1%.
(3) Preparation of avibactam sodium
20g (0.039 mol) of ({ [ (2S,5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) tetrabutylammonium salt was charged into a reaction flask, and then 90g of anhydrous ethanol and 5g of purified water were added thereto and dissolved with stirring.
9.63g (0.047 mol) of sodium isooctanoate and 107.5g of absolute ethanol were added to another bottle, and dissolved by stirring to prepare a solution. And slowly dripping sodium isooctanoate solution into the reaction solution for 4 hours, separating out white solid, stirring for 2 hours, carrying out suction filtration, and washing a filter cake by using absolute ethyl alcohol. 9.10g of abamectin sodium is obtained, and the yield is 80.3%. The purity of the related substances is 98.36%.
Claims (9)
1. A preparation method of avibactam sodium is characterized by comprising the following steps:
(1) weighing a compound IV and an ammonia solution, adding the compound IV and the ammonia solution into a three-necked bottle, stirring for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate to be dry, washing the filtrate with an organic solvent, and drying the filtrate to obtain a compound III;
(2) weighing a compound III and an organic solvent I, stirring, controlling the temperature to be 5-10 ℃, adding N, N-diisopropylethylamine into the system, controlling the temperature to be-5 ℃, dropwise adding chlorosilane, after dropwise adding, heating to be 5-10 ℃, and continuing to control the temperature to react;
(3) after the reaction is finished, adding N, N-carbonyl diimidazole into the reaction system, carrying out heat preservation reaction, after the reaction is finished, adding isopropanol, and continuing temperature control reaction;
(4) controlling the temperature to be 20-30 ℃, directly adding a sulfonation reagent, dropwise adding acid to adjust the pH value, and stirring for reaction after dropwise adding is finished;
(5) then adding 45% tetrabutylammonium salt solution, stirring, respectively adding an extracting agent for extraction twice, mixing the extracted solutions after extraction, and concentrating to dryness; then adding an organic solvent II, stirring for crystallization, transferring into a cold bath, cooling for crystallization, performing suction filtration, and washing; carrying out suction filtration and drying a filter cake; obtaining a compound II;
(6) adding the compound II, the organic solvent III and the purified water into a reaction bottle, stirring and dissolving to obtain a compound II solution, adding the sodium isooctanoate and the organic solvent III into another reaction bottle, and stirring and dissolving to obtain a sodium isooctanoate solution;
slowly dripping the sodium isooctanoate solution into the compound II solution, stirring for reaction after dripping, filtering, washing a filter cake, and drying to obtain the compound I avibactam sodium.
2. The method according to claim 1, wherein in step (1), the compound IV is 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester or oxalate or other salts, preferably 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester oxalate.
3. The production method according to claim 1 or 2, wherein in the step (1), the ammonia solution is a mixed solution of methanol, ethanol, isopropanol, n-propanol or a mixture thereof and ammonia gas; the concentration of the ammonia gas is 7-9 mol/L; the mol ratio of the ammonia to the compound IV is 28-40: 1, preferably 28-36: 1; the organic solvent is one or a mixture of more of ethyl acetate, butyl acetate, ethyl formate or methyl tert-butyl ether, and ethyl acetate is preferred.
4. The preparation method according to claim 1, characterized in that in the step (2), the organic solvent I is one or a mixture of acetonitrile, phenylacetonitrile or propionitrile, preferably acetonitrile; the chlorosilane is dichlorodimethylsilane, dichlorodiphenylsilane, trichloromethylsilane, trichlorophenylsilane or a mixture of one or more of dichlorodimethylsilane, dichlorodiphenylsilane and trichlorophenylsilane, preferably dichlorodimethylsilane; the molar ratio of the chlorosilane to the compound III is 1.20-3.0: 1, preferably 1.20-2.0: 1; the temperature control reaction time is 1-2 h.
5. The method according to claim 1 or 4, wherein in the step (2), the molar ratio of N, N-diisopropylethylamine to the compound III is 1.05-2.0: 1, preferably 1.07-1.2: 1.
6. The method according to claim 1, wherein in step (3), the molar ratio of N, N-carbonyldiimidazole to compound III is 1.1-2.0: 1, preferably 1.1-1.5: 1; the temperature of the heat preservation reaction is 30-35 ℃, the reaction time is 8-15 h, and 8-10 h is preferred; the molar ratio of the isopropanol to the compound III is 3.0-8.0: 1, preferably 4.0-5.0: 1; after the isopropanol is added, the temperature of the temperature-controlled reaction is 30-35 ℃, and the reaction time is 4.0-5.0 h.
7. The process according to claim 1, wherein in the step (4), the sulfonating agent is sulfur trioxide trimethylamine, sulfur trioxide pyridine, N-ethyldiisopropylamine sulfur trioxide complex or sulfur trioxide triethylamine, preferably sulfur trioxide trimethylamine; the molar ratio of the sulfonation reagent to the compound III is 1.0-2.0: 1; the acid is hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof, preferably hydrochloric acid; dropwise adding acid to adjust the pH value to 3-4; the reaction time after the pH is adjusted is 4-6 h.
8. The method according to claim 1, wherein in step (5), the tetrabutylammonium salt solution is tetrabutylammonium acetate, tetrabutylammonium bromide, tetrabutylammonium oxalate, tetrabutylammonium hydroxide, tetrabutylammonium sulfate or a mixture thereof, preferably tetrabutylammonium acetate; the molar ratio of the tetrabutylammonium salt to the compound III is 1.0-2.0: 1, preferably 1.0-1.5: 1; the extractant is dichloromethane, trichloromethane or ethyl acetate, preferably dichloromethane; the organic solvent II is 4-methyl-2-pentanone or ethyl acetate, preferably 4-methyl-2-pentanone; the mass ratio of the organic solvent II to the compound III is 4-7: 1, preferably 4-5: 1; the crystallization temperature is-5 ℃, and the time is 1-2 h.
9. The preparation method according to claim 1, wherein in the step (6), the organic solvent III is ethanol, methanol, isopropanol, n-propanol or a mixture of several of them, preferably ethanol; the molar ratio of the sodium isooctanoate to the compound II is 1.5-3.0: 1, preferably 2.0-2.5: 1; the dropping time of the sodium isooctanoate solution is 2-5 h, preferably 3-4 h; the reaction time is 2-4 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210777931.7A CN115073458A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210777931.7A CN115073458A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115073458A true CN115073458A (en) | 2022-09-20 |
Family
ID=83258129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210777931.7A Pending CN115073458A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115073458A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117486881A (en) * | 2023-12-28 | 2024-02-02 | 成都克莱蒙医药科技有限公司 | Preparation method of avibactam intermediate |
Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005082897A1 (en) * | 2004-01-28 | 2005-09-09 | Pharmacia & Upjohn Company Llc | Oxazolidinone antibacterial agents |
| WO2009097578A1 (en) * | 2008-02-01 | 2009-08-06 | Takeda Pharmaceutical Company Limited | Oxim derivatives as hsp90 inhibitors |
| CN103649051A (en) * | 2011-06-17 | 2014-03-19 | 阿斯利康(瑞典)有限公司 | Process for preparing heterocyclic compounds including trans-7-oxo-6-(sulphooxy)-1, 6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof |
| WO2015097071A1 (en) * | 2013-12-25 | 2015-07-02 | Syngenta Participations Ag | Herbicidal haloalkylsulphonamide derivatives |
| CN105753867A (en) * | 2016-03-24 | 2016-07-13 | 齐鲁制药有限公司 | Preparation method of improved avibactam sodium intermediate compound |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
| CN107540601A (en) * | 2016-06-28 | 2018-01-05 | 新发药业有限公司 | The convenient preparation method of 5R benzyloxies amino piperidine 2S formic acid esters and its oxalates |
| WO2018060484A1 (en) * | 2016-09-30 | 2018-04-05 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
| CN107880042A (en) * | 2016-09-30 | 2018-04-06 | 上海复星星泰医药科技有限公司 | The preparation method of AVM hereinafter Batan sodium and its midbody compound |
| CN108239089A (en) * | 2016-12-27 | 2018-07-03 | 浙江医药股份有限公司新昌制药厂 | A kind of synthetic method of AVM hereinafter Batan sodium |
| US20190152953A1 (en) * | 2015-08-06 | 2019-05-23 | Ube Industries, Ltd. | Substituted guanidine derivatives |
| WO2019122442A1 (en) * | 2017-12-22 | 2019-06-27 | Centre National De La Recherche Scientifique | New beta-lactamase inhibitors targeting gram negative bacteria |
| WO2019122438A1 (en) * | 2017-12-22 | 2019-06-27 | Centre National De La Recherche Scientifique | New antibiotics targeting mycobacteria |
| CN109956941A (en) * | 2017-12-25 | 2019-07-02 | 新发药业有限公司 | A kind of simple and convenient process for preparing of AVM hereinafter Batan |
| CN111196807A (en) * | 2018-11-20 | 2020-05-26 | 齐鲁制药有限公司 | Recovery preparation method of avibactam sodium |
| CN114656465A (en) * | 2020-12-23 | 2022-06-24 | 南京佰麦生物技术有限公司 | Preparation method of avibactam sodium |
-
2022
- 2022-07-04 CN CN202210777931.7A patent/CN115073458A/en active Pending
Patent Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005082897A1 (en) * | 2004-01-28 | 2005-09-09 | Pharmacia & Upjohn Company Llc | Oxazolidinone antibacterial agents |
| WO2009097578A1 (en) * | 2008-02-01 | 2009-08-06 | Takeda Pharmaceutical Company Limited | Oxim derivatives as hsp90 inhibitors |
| CN103649051A (en) * | 2011-06-17 | 2014-03-19 | 阿斯利康(瑞典)有限公司 | Process for preparing heterocyclic compounds including trans-7-oxo-6-(sulphooxy)-1, 6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof |
| WO2015097071A1 (en) * | 2013-12-25 | 2015-07-02 | Syngenta Participations Ag | Herbicidal haloalkylsulphonamide derivatives |
| US20190152953A1 (en) * | 2015-08-06 | 2019-05-23 | Ube Industries, Ltd. | Substituted guanidine derivatives |
| CN105753867A (en) * | 2016-03-24 | 2016-07-13 | 齐鲁制药有限公司 | Preparation method of improved avibactam sodium intermediate compound |
| CN107540601A (en) * | 2016-06-28 | 2018-01-05 | 新发药业有限公司 | The convenient preparation method of 5R benzyloxies amino piperidine 2S formic acid esters and its oxalates |
| CN107880042A (en) * | 2016-09-30 | 2018-04-06 | 上海复星星泰医药科技有限公司 | The preparation method of AVM hereinafter Batan sodium and its midbody compound |
| WO2018060484A1 (en) * | 2016-09-30 | 2018-04-05 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
| CN108239089A (en) * | 2016-12-27 | 2018-07-03 | 浙江医药股份有限公司新昌制药厂 | A kind of synthetic method of AVM hereinafter Batan sodium |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
| WO2019122442A1 (en) * | 2017-12-22 | 2019-06-27 | Centre National De La Recherche Scientifique | New beta-lactamase inhibitors targeting gram negative bacteria |
| WO2019122438A1 (en) * | 2017-12-22 | 2019-06-27 | Centre National De La Recherche Scientifique | New antibiotics targeting mycobacteria |
| CN109956941A (en) * | 2017-12-25 | 2019-07-02 | 新发药业有限公司 | A kind of simple and convenient process for preparing of AVM hereinafter Batan |
| WO2019127903A1 (en) * | 2017-12-25 | 2019-07-04 | 新发药业有限公司 | Simple preparation method for avibactam |
| CN111196807A (en) * | 2018-11-20 | 2020-05-26 | 齐鲁制药有限公司 | Recovery preparation method of avibactam sodium |
| CN114656465A (en) * | 2020-12-23 | 2022-06-24 | 南京佰麦生物技术有限公司 | Preparation method of avibactam sodium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117486881A (en) * | 2023-12-28 | 2024-02-02 | 成都克莱蒙医药科技有限公司 | Preparation method of avibactam intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20210032950A (en) | Chemical method for preparing phenylpiperidinyl indole derivatives | |
| CN105753867A (en) | Preparation method of improved avibactam sodium intermediate compound | |
| CN105131017A (en) | Preparation method for cefcapene pivoxil hydrochloride | |
| CN115073458A (en) | Preparation method of avibactam sodium | |
| US20190023681A1 (en) | Method and intermediate for preparing tulathromycin | |
| JP2021536497A (en) | Manufacturing process of amantadine nitrate ester derivative | |
| KR102238179B1 (en) | Simple manufacturing method of abibactam | |
| US20020095034A1 (en) | Imipenem production process | |
| CN110551144A (en) | Preparation method of amoxicillin | |
| CN113025679B (en) | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| KR100343434B1 (en) | Method of preparing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid | |
| CN107324998B (en) | Method for preparing external antibiotic drug Retapamulin | |
| KR910003709B1 (en) | Process for the preparation of butyl 3'-(1h-tetrazole-5-yl)oxanylrate | |
| CN102174047A (en) | Novel process for preparing doripenem | |
| CN108299470B (en) | Preparation method of cefteram pivoxil | |
| AU2021297767A1 (en) | Preparation method for aromatic ether compound | |
| CN110590775A (en) | Preparation method of intermediate of Abamebactam sodium of beta-lactamase inhibitor drug | |
| CN111592553A (en) | Method for preparing moxidectin | |
| CN101891666B (en) | Preparation method of intermediate of beta methylcarbapenem antibiotics | |
| CN111675641B (en) | Monocyclic beta-lactam compound, monocyclic lactam compound salt and preparation method thereof | |
| CN102304129A (en) | Method suitable for industrially producing tebipenem | |
| CN111039963B (en) | WXFL10203614 water-soluble analogue and synthetic method thereof | |
| CN117551150A (en) | Ai Tuoge column cleaner synthesis method | |
| KR100400498B1 (en) | Novel method for preparation of cephem derivatives or salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |