CN111732587B - Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof - Google Patents
Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof Download PDFInfo
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Abstract
An avermectin intermediate compound disulfonic acid gemini quaternary ammonium salt and a preparation method thereof relate to medical compounds and organic chemical synthesis, and the preparation method of the avermectin intermediate comprises the following steps: (1) (2S, 5R) -6-hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide is subjected to hydrogenolysis sulfonation reaction; (2) After the reaction in the previous step is completed, washing the filtrate by suction filtration once, and adding gemini quaternary ammonium salt for reaction; and (3) after the reaction in the previous step is completed, extracting, rotary steaming and crystallizing. Compared with the prior art, the method has the advantages of simple operation, easily obtained raw materials, low cost, less consumption of the gemini quaternary ammonium salt, high purity of the obtained gemini quaternary ammonium disulfonate, and over 99.5% of the relative purity of the avibactam sodium HPLC generated by the gemini quaternary ammonium disulfonate through sodium salt exchange, so that the process is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of pharmaceutical compounds and organic chemical synthesis, in particular to an avibactam intermediate compound and a preparation method thereof.
Background
Avibactam sodium, chemical name: [ (1R, 2S, 5R) -2- (aminocarbonyl) -7-oxo-1,6-diazabicyclo [3.2.1] oct-6-yl ] sulfuric acid-sodium salt, is a diazabicyclooctanone compound, which is a novel beta-lactamase inhibitor and is effective in inhibiting class A, class C and partial class D beta-lactamases. In 2015, the compound preparation of abamectin and ceftazidime is approved by the FDA of the United states to be used for treating severe infection caused by drug-resistant bacteria, and the action effect of the compound preparation is obviously higher than that of marketed clavulanic acid, sulbactam and tazobactam. Therefore, the avibactam has wide application prospect, but the difficulty in synthesizing the avibactam greatly hinders the industrial production and wider application of the avibactam.
At present, a plurality of literature reports are available for the synthesis of avibactam sodium, and the literature reports are as follows: CN103649051B, CN106699756A, CN106831772A, and the like. The preparation method is as follows:
in the prior art, a single-season ammonium salt is mostly adopted, for example, in patent CN103649051B of Alixican, tetrabutylammonium acetate is taken as an ammonium reagent to be combined with sulfonic acid, and then sodium salt exchange is carried out to obtain the avibactam sodium. However, quaternary ammonium salts such as tetrabutylammonium acetate and the like have poor combination effect with sulfonic acid, higher feeding equivalent and more expensive raw materials, and the purity of the quaternary ammonium sulfonate intermediate is not high, so that the production cost is increased, and certain influence is brought to the quality of subsequent products. Meanwhile, the route uses n-butyl acetate with high boiling point to wash a reaction system and a toxic crystallization solvent 4-methyl-2-pentanone, so that residual solvent is not easy to remove, the operation is complicated, and the subsequent product quality of the avibactam sodium is influenced. Therefore, this route is not conducive to industrial scale-up.
Disclosure of Invention
In order to solve the defects of the prior art, the invention discloses an avibactam intermediate disulphonic acid gemini quaternary ammonium salt and a synthesis method thereof, and avibactam sodium is synthesized by using the intermediate. The specific synthesis process is as follows:
R 1 selected from methylene, ethylene, propylene, butylene, disubstituted phenyl, disubstituted biphenyl, disubstituted heterocyclyl; r 2 ，R 3 ，R 4 Identical or different, the radicals are selected from methyl, ethyl, propyl, butyl, pentyl.
The technical scheme of the invention is as follows:
(1) Dissolving (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide in alcohol and water, introducing hydrogen to remove benzyl, and then reacting with a sulfonation reagent to perform sulfonation;
(2) Once washed, (2s, 5r) -6- (sulfooxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide is reacted with a gemini quaternary ammonium salt;
(3) After the reaction is finished, extracting, rotary steaming, crystallizing, filtering and drying to obtain the sulfonic acid quaternary ammonium salt intermediate compound shown as the formula (I).
The invention relates to a synthetic method of an avibactam intermediate, which specifically comprises the following steps: firstly, (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide is taken as a raw material, is dissolved in a mixed solvent of isopropanol and water, is introduced with hydrogen to remove benzyl under the condition that palladium carbon is taken as a catalyst, and then is subjected to sulfonation reaction with a sulfonation reagent; after the reaction is completed, washing once by using ethyl acetate, firstly adding 72% of gemini quaternary ammonium salt for reaction, and after the reaction is completed, extracting a product by using dichloromethane; then adding water and isopropanol, adding 28% quaternary ammonium salt for continuous reaction, and extracting with dichloromethane after complete reaction; and combining and concentrating the extract, adding a solvent for crystallization, performing suction filtration and drying to obtain the disulfonic acid gemini quaternary ammonium salt intermediate compound shown as the formula (I).
In the step (1), the catalyst is palladium carbon, preferably 10% palladium carbon; the reaction temperature is 15-35 ℃; the reaction time is 1-8h;
(2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide is dissolved in a mixed solution of alcohol and water, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol, preferably isopropanol, and the volume ratio of the alcohol to the water is 1:1;
the gemini quaternary ammonium salt is N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexabutyl-1,4-butanediammonium bromide, N 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 -hexabutyl-1,5-pentanediammonium bromide, N 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 -hexabutyl-1,6-hexanediammonium bromide, N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexapropyl-1,4-butanediammonium bromide, N 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 -hexapropyl-1,5-Pentanediammonium bromide, N 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 Hexapropyl-1,6 hexane diammonium bromide, 4,4 '-bis (tripropylmethylammonium) -1,1' -biphenyl dichloride, 5,5 '-bis (tributylmethylammonium) -1,1' -biphenyl dichloride, and the like.
The feeding ratio of the gemini quaternary ammonium salt to (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide is 0.5-1.5; the reaction temperature is 25-45 ℃ and the reaction time is 1-5h.
The crystallization solvent is selected from ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-ethyl acetate, and its ratio is 1:1-10, preferably 1:5; the crystallization temperature is 0-5 ℃.
The invention relates to a method for synthesizing avibactam sodium by using an intermediate. Dissolving the obtained disulfonic acid gemini quaternary ammonium salt intermediate in ethanol or acetonitrile, adding ethanol or acetonitrile solution of sodium isooctanoate, separating out white solid, filtering and drying to obtain the avibactam sodium, wherein the relative purity of the obtained avibactam sodium is more than 99.5% through ethanol washing HPLC.
Compared with the prior art, the process has the advantages of simple operation, easily obtained raw materials, lower cost and higher product purity, and the avibactam sodium obtained by sodium salt exchange is easily purified to obtain a final product with higher purity, so the process is favorable for industrial scale-up production.
Drawings
FIG. 1 shows a method for preparing a gemini quaternary ammonium disulfonate compound 1 1 H NMR
FIG. 2 shows a method for preparing a gemini quaternary ammonium disulfonate compound 1 13 C NMR
The specific implementation mode is as follows:
the invention will be further elucidated and described with reference to the drawings.
Example 1
Reacting (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g)1.00 eq), 10% palladium on carbon (0.05 g, q), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen gas was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, the filtrate was washed once with ethyl acetate (12 ml) and then N was added 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 Hexabutyl-1,4-butanediammonium bromide (2.60g, 0.61eq), maintained at 40 ℃ for the reaction. Extracting with dichloromethane (12 ml × 2), combining organic phases, performing rotary evaporation, adding a mixed solvent of ethanol and ethyl acetate, performing crystallization, filtering, washing and drying to obtain the averbactam intermediate gemini quaternary ammonium disulfonate compound 1 (2.42 g, the yield is 70%) and the relative purity of HPLC (high performance liquid chromatography) is 99.6%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 1 (2.42g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.68g, 4eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 1, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (1.25 g, the yield is 86 percent) and the relative purity of HPLC (high performance liquid chromatography) is 99.9 percent.
Example 2
Reacting (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, ca.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen gas was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 Hexabutyl-1,4-butanediammonium bromide (1.87g, 0.44eq), kept at 40 ℃ for reaction. Extraction was carried out with methylene chloride (10 ml), and 28% N was added 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 Hexabutyl-1,4-butanediammonium bromide (0.73g, 0.17eq), kept at 40 ℃, extracted with dichloromethane (10 ml), combined dichloromethane phases and rotary evaporated, added ethyl acetate solvent for crystallization, filteredAnd drying to obtain the intermediate of the abamectin gemini quaternary ammonium disulfonate compound 1 (2.85 g, the yield is 82%) and the relative purity of HPLC (high performance liquid chromatography) is 99.7%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 1 (2.85g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.98g, 4 eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 1, white solid is separated out through reaction, and the abamectin sodium (1.39 g, 81 percent of yield) and the HPLC relative purity is 99.8 percent after filtration and drying.
Example 3
The reaction product of (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, wt.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 Hexabutyl-1,4-butanediammonium bromide (1.87g, 0.44eq), kept at 40 ℃ for reaction. Extracting with dichloromethane (10 ml), adding water (4 ml) and isopropanol (4 ml) to the aqueous phase, adding 28% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexabutyl-1,4-butanediammonium bromide (0.73g, 0.17eq), kept at 40 ℃ for reaction, extracted with dichloromethane (10 ml), combined with dichloromethane phases and rotary evaporated, added with ethyl acetate solvent for crystallization, filtered and dried to obtain the averbactam intermediate gemini quaternary ammonium disulfonate compound 1 (2.88 g, yield 83%), relative purity of HPLC 99.5%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 1 (2.88g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.98g, 4 eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 1, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (1.38 g, the yield is 80%) and the relative purity of HPLC (high performance liquid chromatography) is 99.8%.
Example 4
Reacting (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, wt.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 Hexabutyl-1,4-butanediammonium bromide (1.87g, 0.44eq), kept at 40 ℃ for reaction. Extracting with dichloromethane (10 ml), adding water (4 ml) and isopropanol (4 ml) to the aqueous phase, adding 28% N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexabutyl-1,4-butanediammonium bromide (0.73g, 0.17eq), kept at 40 ℃ for reaction, extracted with dichloromethane (10 ml), the dichloromethane phases were combined and spin-dried to an oil, ethanol (10 ml) was added, a solution of sodium isooctanoate (2.41g, 2eq) in ethanol (10 ml) was added dropwise to the ethanol solution of disulfonic acid gemini quaternary ammonium salt compound 1, reacted to precipitate a white solid, filtered and dried to obtain avibactam sodium (1.41 g, 68% over two steps) with a HPLC relative purity of 99.9%.
Example 5
The reaction product of (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, ca.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen gas was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 Hexabutyl-1,5 pentanediammonium bromide (1.92g, 0.44eq) was reacted at 40 ℃. Extraction was carried out with methylene chloride (10 ml), and 28% N was added 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 Hexabutyl-1,5 pentanediammonium bromide (0.75g, 0.17eq), kept at 40 ℃, extracted with dichloromethane (10 ml), combined dichloromethane phases and rotary evaporatedAdding methyl tert-butyl ether solvent for crystallization, filtering and drying to obtain the averbactam intermediate gemini quaternary ammonium disulfonate compound 2 (2.58 g, the yield is 73 percent), and the relative purity of HPLC is 99.4 percent.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 2 (2.00g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.37g, 4eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 3, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (1.02 g, the yield is 86 percent) and the relative purity of HPLC (high performance liquid chromatography) is 99.6 percent.
Example 6
Reacting (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, wt.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 Hexabutyl-1,6-hexanediammonium bromide (1.96g, 0.44eq) was reacted at 40 ℃. Extraction was carried out with methylene chloride (10 ml), and 28% N was added 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 -hexabutyl-1,6-hexanediammonium bromide (0.76g, 0.17eq), reacting at 40 ℃, extracting with dichloromethane (10 ml), combining dichloromethane phases and rotary evaporating, adding methyl tert-butyl ether solvent for crystallization, filtering and drying to obtain the averbactam intermediate gemini quaternary ammonium disulfonate compound 3 (2.69 g, yield 75%), relative purity of HPLC 99.5%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 3 (2.00g, 1.00eq), is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.35g, 4eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 3, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (1.04 g, 89% yield) with the relative purity of HPLC (high performance liquid chromatography) of 99.6%.
Example 7
Reacting (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1]Octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, wt.), trimethylamine trioxide complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% N was added 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 Hexapropyl-1,5 pentanediammonium bromide (1.65g, 0.44eq) was reacted at 40 ℃. Extraction was performed with dichloromethane (10 ml) and 28% N was added 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 -hexapropyl-1,5-pentane diammonium bromide (0.64g, 0.17eq), reacting at 40 ℃, extracting with dichloromethane (10 ml), combining dichloromethane phases and evaporating in a rotary manner, adding methyl tert-butyl ether solvent for crystallization, filtering and drying to obtain averbactam intermediate gemini quaternary ammonium disulfonate compound 4 (1.50 g, yield 47%), and relative purity of HPLC 99.5%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 4 (1.00g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (0.75g, 4eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 4, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (0.48 g, the yield is 74%) and the relative purity of HPLC (high performance liquid chromatography) is 99.7%.
Example 8
(2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, q.), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen gas was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% of 4,4 '-bis (tripropylmethylammonium) -1,1' -biphenyl dichloride (1.72g, 0.44eq) was added and the reaction was maintained at 40 ℃. Extracting with dichloromethane (10 ml), adding 28% of 4,4 '-bis (tripropyl methyl ammonium) -1,1' -biphenyl dichloride (0.68g, 0.17eq), reacting at 40 ℃, extracting with dichloromethane (10 ml), combining dichloromethane phases, evaporating in a rotary manner, adding methyl tert-butyl ether solvent for crystallization, filtering and drying to obtain averbactam intermediate gemini quaternary ammonium disulfonate compound 5 (2.26 g, yield 63%), and HPLC relative purity 99.6%.
Dissolving the averbactam intermediate gemini quaternary ammonium disulfonate compound 5 (1.00g, 1.00eq) in ethanol (10 ml), dropwise adding the ethanol (10 ml) solution of sodium isooctanoate (1.34g, 4eq) into the ethanol solution of the gemini quaternary ammonium disulfonate compound 5, reacting to precipitate white solid, filtering and drying to obtain the averbactam sodium (0.85 g, yield 74%), and relative purity of HPLC (99.8%).
Example 9
(2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide (2.00 g,1.00 eq), 10% palladium on carbon (0.05 g, q.), sulfur trioxide trimethylamine complex (1.13g, 1.12eq), triethylamine (0.20ml, 0.2eq), isopropanol (8 ml) and water (8 ml) were sequentially added to a 50ml reaction flask, and hydrogen gas was introduced under stirring to complete the reaction. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, once with ethyl acetate (12 ml) and then 72% of 5,5 '-bis (tributylmethylammonium) -1,1' -biphenyl dichloride (1.98g, 0.44eq) was added and the reaction was maintained at 40 ℃. Extracting with dichloromethane (10 ml), adding 28% 5,5 '-bis (tributylmethylammonium) -1,1' -biphenyl dichloride (0.77g, 0.17eq), reacting at 40 deg.C, extracting with dichloromethane (10 ml), combining dichloromethane phases, evaporating in a rotary manner, adding methyl tert-butyl ether solvent for crystallization, filtering and drying to obtain the averbactam intermediate gemini quaternary ammonium disulfonate compound 6 (2.77 g, yield 71%), and relative purity of HPLC 99.3%.
The intermediate of abamectin, namely the gemini quaternary ammonium disulfonate compound 6 (1.00g, 1.00eq) is dissolved in ethanol (10 ml), the ethanol (10 ml) solution of sodium isooctanoate (1.23g, 4 eq) is dripped into the ethanol solution of the gemini quaternary ammonium disulfonate compound 6, white solid is separated out by reaction, and the obtained product is filtered and dried to obtain abamectin sodium (0.75 g, the yield is 70 percent) and the relative purity of HPLC (high performance liquid chromatography) is 99.5 percent.
Claims (9)
1. An abamectin intermediate compound gemini quaternary ammonium disulfonate is characterized in that: the structural formula of the disulphonic acid gemini quaternary ammonium salt of the intermediate compound of the abamectin is shown as the formula (I):
wherein R is 1 Selected from methylene, ethylene, propylene, butylene; r 2 ，R 3 ，R 4 Identical or different, the radicals are selected from methyl, ethyl, propyl, butyl, pentyl;
or the gemini quaternary ammonium salt is 4,4 '-bis (tripropyl methyl ammonium) -1,1' -biphenyl or 5,5 '-bis (tributyl methyl ammonium) -1,1' -biphenyl.
2. The preparation method of the averbactam intermediate compound gemini quaternary ammonium disulfonate disclosed by claim 1 is characterized by comprising the following steps of:
step (1) (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide is dissolved in alcohol and water, is introduced with hydrogen to remove benzyl, and then reacts with a sulfonation reagent to perform sulfonation;
washing once in the step (2), (2S, 5R) -6- (sulfooxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide reacts with a part of gemini quaternary ammonium salt, and extracting a product by using dichloromethane; then adding water and isopropanol, and then adding the other part of gemini quaternary ammonium salt for continuous reaction;
and (3) after the reaction in the step (3) is finished, performing secondary extraction by using dichloromethane, combining and concentrating the two extraction liquids, performing rotary evaporation, adding a solvent for crystallization to obtain a white solid, performing suction filtration, and drying to obtain an intermediate compound, namely the disulfo-gemini quaternary ammonium salt of abamectin.
3. The method according to claim 2, wherein (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide is firstly used as a raw material, dissolved in a mixed solvent of isopropanol and water, introduced with hydrogen to remove benzyl under the condition of palladium-carbon as a catalyst, and then subjected to sulfonation reaction with a sulfonation reagent; after the reaction is completed, washing once by using ethyl acetate, firstly adding 72% of gemini quaternary ammonium salt for reaction, and after the reaction is completed, extracting a product by using dichloromethane; then adding water and isopropanol, adding 28% of quaternary ammonium salt for continuous reaction, and extracting with dichloromethane after the reaction is complete; and combining and concentrating the extract liquor, adding a solvent for crystallization, performing suction filtration and drying to obtain an intermediate compound, namely the disulphonic acid gemini quaternary ammonium salt of the abamectin.
4. The method according to claim 2, wherein in the step (1), the catalyst is palladium carbon, and the reaction temperature is 15-35 ℃; the reaction time is 1-8h;
(2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide is dissolved in a mixed solution of alcohol and water, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol, and the volume ratio of the alcohol to the water is 1:1.
5. The method of claim 2 wherein the gemini quaternary ammonium salt is N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexabutyl-1,4-butanediammonium bromide, N 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 -hexabutyl-1,5-pentanediammonium bromide, N 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 Hexabutyl-1,6 Hexane diammonium bromide, N 1 ,N 1 ,N 1 ,N 4 ,N 4 ,N 4 -hexapropyl-1,4-butanediammonium bromide, N 1 ,N 1 ,N 1 ,N 5 ,N 5 ,N 5 -hexapropyl-1,5-Pentanediammonium bromide, N 1 ,N 1 ,N 1 ,N 6 ,N 6 ,N 6 -hexapropyl-1,6-hexanediammonium bromide, 4,4 '-bis (tripropylmethylammonium) -1,1' -biphenyl dichloride, 5,5 '-bis (tributylmethylammonium) -1,1' -biphenyl dichloride.
6. The process according to claim 2, wherein the charge ratio of gemini quaternary ammonium salt to (2s, 5r) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxamide is 0.5 to 1.5; the reaction temperature is 25-45 ℃, and the reaction time is 1-5h.
7. The method according to claim 2, wherein the crystallization solvent is selected from the group consisting of ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-ethyl acetate, in a volume ratio of 1:1-10; the crystallization temperature is 0-5 ℃.
8. The method of claim 7, wherein the ratio of the front volume to the back volume is 1:5.
9. The method for preparing avibactam by using gemini quaternary ammonium disulfonate of claim 1,
dissolving the obtained disulfonic acid gemini quaternary ammonium salt intermediate into ethanol or acetonitrile, adding ethanol or acetonitrile solution of sodium isooctanoate, separating out white solid, filtering and drying to obtain the avibactam sodium.
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