CN112679498B - Quaternary ammonium sulfonate compound and preparation method and application thereof - Google Patents
Quaternary ammonium sulfonate compound and preparation method and application thereof Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
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- C07D295/037—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements with quaternary ring nitrogen atoms
Abstract
The invention provides a sulfonic acid quaternary ammonium salt compound, a preparation method and application thereof, wherein the compound is a compound shown as a formula (I), n is equal to 1And the 2,3,R group is selected from propyl, butyl, pentyl. The detection purity of the quaternary ammonium sulfonate compound prepared by the invention is more than 99.89%. The beta-lactamase inhibitor avibactam sodium prepared by the novel ammonium sulfonate compound has the purity of more than 99.90 percent, meets the pharmaceutical quality standard of raw material medicines, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of medical compounds and synthetic methods thereof, in particular to a sulfonic acid quaternary ammonium salt compound of a beta-lactamase inhibitor, a preparation method thereof and application thereof as an intermediate in preparing the beta-lactamase inhibitor.
Background
A compound of formula (ii), chemically known as ({ [ (2s,5r) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) quaternary ammonium salt, is an important intermediate in the production of avibactam (avibactam) in the synthesis of beta-lactamase inhibitors disclosed in CN 103649051A, CN 105283458B patents. Therefore, the preparation of the quaternary ammonium sulfonate with high purity and high yield can greatly improve the production quality of abamectin and reduce the production cost.
The compound of formula (II) is an important intermediate for synthesizing beta-lactamase inhibitor, such as avibactam medicine. The preparation of the compound of the formula (II) with high purity and high yield is very important in the aspect of producing the avibactam sodium and other novel azabicyclo sulfonic acid compounds.
Disclosure of Invention
The first object of the present invention is to provide a novel quaternary ammonium sulfonate compound (formula II);
a second object of the present invention is to provide a method for preparing a quaternary ammonium sulfonate compound, comprising:
(1) Dissolving (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, sulfur trioxide trimethylamine and triethylamine in alcohol and water, adding a catalyst, introducing hydrogen to remove benzyl, and then performing sulfonation reaction with a sulfonation reagent;
(2) The method a comprises the following steps: completely reacting, filtering to remove palladium carbon, removing alcohol by rotary evaporation, adding a solvent, (2S, 5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide and quaternary ammonium bromide for reaction and crystallization;
the method b: ethyl acetate is washed once, (2S, 5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide reacts with 60 percent of the total mass of quaternary ammonium salt, and products are extracted by dichloromethane; then adding water and isopropanol, adding 40% of the total mass of the quaternary ammonium salt for continuous reaction, extracting by dichloromethane, combining the two extraction liquids, carrying out rotary evaporation, adding a solvent for crystallization.
(3) After the reaction is finished, carrying out suction filtration and drying to obtain a sulfonic acid quaternary ammonium salt compound formula (II);
the third purpose of the invention is to provide the application of preparing the high-purity avibactam sodium product by using the sulfonic acid quaternary ammonium salt formula (II), which comprises the following steps: dissolving a sulfonic acid quaternary ammonium salt compound in absolute ethyl alcohol, dropwise adding an ethanol solution of sodium isooctanoate at room temperature, reacting for 3 hours at room temperature after dropwise adding to obtain a white solid, and performing suction filtration, drying and HPLC detection to obtain the product with the purity of 99.93 percent.
The detailed description is directed to specific inventive steps:
in general, we provide a novel quaternary ammonium sulfonate compound of formula (ii):
in the second aspect of the present invention, there is provided a synthesis method for preparing the quaternary ammonium sulfonate compound, comprising:
in the step (1), (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, sulfur trioxide trimethylamine, triethylamine were dissolved in a mixed solution of alcohol and water, and a catalyst was added to the mixed solution, (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, sulfur trioxide trimethylamine, triethylamine in a molar ratio of 1:1.12:0.2, the catalyst is palladium carbon containing 10 percent of palladium and 50 percent of water content, the dosage of the catalyst is 0.025 times of the mass of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, the reaction temperature is 20-35 ℃, the reaction time is 1-8h, the reaction solvent is selected from methanol-water, ethanol-water or isopropanol-water mixed solvent, preferably isopropanol and water mixed solvent, and the volume ratio of the reaction solvent is 1:1;
in the method a in the step (2), the rotary evaporation temperature is 25-60 ℃, preferably 45 ℃, the molar ratio of (2S, 5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide to quaternary ammonium bromide is 1 (1-1.3), the added solvent accounts for 1-15% of the volume of the residual solvent for removing the alcohol, the solvent is selected from acetonitrile, 1, 4-dioxane, acetone, tetrahydrofuran and water, preferably 5%, the reaction crystallization temperature is-5-10 ℃, and the reaction crystallization time is 1-5h.
In the method b in the step (2), the amount of ethyl acetate is 5 times of the mass of (2s, 5r) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, the amounts of water and isopropanol added are 2.4 times of the mass of (2s, 5r) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, respectively, and the reaction crystallization solvent is selected from ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-ethyl acetate, preferably ethanol and ethyl acetate, and the volume ratio of the crystallization solvent is 2:1-4:1, preferably 3:1, the crystallization temperature is 0-5 ℃.
The third purpose of the invention is to provide the application of preparing the high-purity avibactam sodium product by using the sulfonic acid quaternary ammonium salt compound shown as the formula (II), which comprises the following steps: dissolving 1 molar equivalent of quaternary ammonium sulfonate compound in absolute ethyl alcohol, dropwise adding 2 molar equivalent of ethanol solution of sodium isooctanoate at room temperature, reacting for 3 hours after the dropwise adding is finished to obtain white solid, performing suction filtration, and drying to obtain the abamectin sodium, wherein the purity of the abamectin sodium is 99.93% by HPLC detection.
The invention provides a novel quaternary ammonium sulfonate compound, a preparation method and application thereof, and the preparation method has the advantages of simple operation, low cost, high greenness and suitability for production amplification.
Drawings
FIG. 1 is a hydrogen spectrum diagram of quaternary ammonium sulfonate
FIG. 2 is a carbon spectrum diagram of quaternary ammonium sulfonate
The specific implementation mode is as follows:
a preparation method of an avibactam intermediate is characterized by comprising the following steps: the structural formula of the avibactam intermediate is shown as the formula (I):
wherein n is equal to 1,2,3 (five-membered, six-membered, seven-membered ring), and the R group is selected from propyl, butyl, pentyl; a process for the preparation of a compound of formula (i) comprising the steps of:
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 reacting with a sulfonation reagent to sulfonate;
washing once in the step (2), (2S, 5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide with 60% quaternary ammonium salt, and extracting the product with dichloromethane; then adding part of water and isopropanol, and then adding the remaining 40% of quaternary ammonium salt for continuous reaction;
after the reaction in the step (3) is finished, performing secondary extraction by using dichloromethane, combining and concentrating the extract liquor, performing rotary evaporation, adding a solvent for crystallization to obtain a white solid, performing suction filtration and drying to obtain a sulfonic acid quaternary ammonium salt intermediate compound shown in the formula (I);
further, the catalyst is palladium carbon, the reaction temperature is 20-35 ℃, and the reaction time is 1-8h; the reaction solvent is a mixed solvent of methanol-water, ethanol-water, isopropanol-water and the like.
Further, in said formula (I) n is equal to 3 and the R group is pentyl.
Further, the product obtained in the step (1) is washed once by ethyl acetate, and the feeding ratio of the quaternary ammonium salt to the (2S, 5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is 1.2-1.5: the reaction temperature is 30-45 ℃ and the reaction time is 1-5h.
Further, the reaction crystallization solvent is ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-ethyl acetate; the crystallization solvent ratio is 2:1-4:1, the crystallization temperature is 0-5 ℃. Further, dissolving the obtained quaternary ammonium sulfonate intermediate in ethanol or acetonitrile, adding an ethanol or acetonitrile solution of sodium isooctanoate, separating out a white solid, filtering and drying to obtain the abamectin sodium.
Example 1
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced with stirring and the reaction was completed at 25 ℃. Filtering to remove palladium carbon, washing filter cake with water, washing filtrate once with 25ml ethyl acetate, adding 60% 1, 1-dipentyl hexamethylene ammonium bromide (4.2 g) and keeping 40 ℃ for reaction, and extracting with dichloromethane (25 ml multiplied by 2); water (12 ml) and isopropyl alcohol (12 ml) were added thereto, and the remaining 40% of 1, 1-dipentylcyclohexylideneammonium bromide (2.8 g) was added thereto, reacted while maintaining the temperature at 40 ℃ and extracted with methylene chloride (25 ml. Times.2). The combined organic phases were rotary evaporated, added with ethyl acetate and ethanol (1. (yield 68%)
1 H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).
13 C NMR(101MHz,Chloroform-d)δ172.30,166.13,62.98,61.21,60.44,57.92,47.97,28.39,27.58,22.15,22.07,21.82,20.79,17.36,13.81.
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
Weighing 5g of quaternary ammonium sulfonate and dissolving the quaternary ammonium sulfonate in ethanol (25 ml), dropwise adding an ethanol solution of sodium isooctanoate (3.3 g, 2eq) into the ethanol solution of the quaternary ammonium sulfonate, precipitating a white solid, filtering and drying to obtain 2.5g of abamectin sodium (yield 88%).
1 HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13 C NMR(100MHz,D 2 O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
Example 2
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was carried out at 25 ℃ until completion. Filtering to remove palladium carbon, washing filter cake with water, washing primary filtrate with 25ml ethyl acetate, adding 60% 1, 1-dipentyl cyclohexylammonium bromide (4.2 g) and reacting under the condition of keeping 40 ℃, and extracting with dichloromethane (25 ml multiplied by 2); water (12 ml) and isopropyl alcohol (12 ml) were added thereto, and the remaining 40% of 1, 1-dipentylcyclohexylideneammonium bromide (2.8 g) was added thereto, reacted while maintaining the temperature at 40 ℃ and extracted with methylene chloride (25 ml. Times.2). The combined organic phases are evaporated by rotation, ethanol (30 ml) is added for dissolving, then ethanol solution of sodium isooctanoate (3.3 g, 2eq) is added dropwise, white solid is separated out, and the white solid is filtered and dried to obtain 3.17g of abamectin sodium. (two-step yield 61%)
1 HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13 C NMR(100MHz,D 2 O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
Example 3
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5g, 18.2mmol), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was carried out at 25 ℃ until completion. Filtering to remove palladium carbon, washing filter cake with water, removing isopropanol by rotary evaporation at 45 deg.C, adding 5% acetonitrile (volume ratio of the rest system), adding 1, 1-dipentyl cyclohexylammonium bromide (7g, 1.1eq), and reacting at 0 deg.C for crystallization for 3h. Filtration and drying gave 8g of ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dipentylcyclo-hexamethylene ammonium salt) (yield: 87%).
1 H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).
13 C NMR(101MHz,Chloroform-d)δ172.30,166.13,62.98,61.21,60.44,57.92,47.97,28.39,27.58,22.15,22.07,21.82,20.79,17.36,13.81.
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
Dissolving 3g of ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dipentyl cyclohexylammonium salt) in absolute ethanol, dropwise adding an ethanol solution of sodium isooctanoate at room temperature, reacting for 3 hours after dropwise adding to obtain a white solid, and carrying out suction filtration, drying and HPLC detection. (yield: 90%, purity: 99.92%).
1HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
Example 4
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5g, 18.2mmol), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring at 25 ℃ until the reaction was complete. The palladium-carbon was removed by suction filtration, the filter cake was washed with water, isopropanol was removed by rotary evaporation at 45 ℃ and 5% tetrahydrofuran was added, followed by addition of 1, 1-dibutyl-cyclohexamethyleneammonium bromide (6.4g, 1.2eq) and reaction crystallization was carried out at 0 ℃. Filtering, and drying to obtain 7g ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dibutyl cyclohexylammonium salt) (yield 80%)
1 H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.71–3.64(m,4H),3.47–3.39(m,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),2.08–1.97(m,4H),1.93–1.84(m,1H),1.71(dd,J＝10.4,5.9Hz,4H),1.34(td,J＝6.4,5.7,2.7Hz,8H),0.95–0.85(m,6H).
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
3g of ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dibutyl cyclohexylammonium salt) is dissolved in absolute ethyl alcohol, an ethanol solution of sodium isooctanoate is dropwise added at room temperature, reaction is carried out for 3 hours after dropwise addition is finished, and white solid is obtained, filtered, dried and detected by HPLC. (yield: 91%, purity: 99.94%).
1HNMR(500MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
Example 5
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5g, 18.2mmol), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was carried out at 25 ℃ until completion. Filtering to remove palladium carbon, washing filter cake with water, removing isopropanol by rotary evaporation at 45 deg.C, adding 5% 1, 4-dioxane, adding 1, 1-dipentyltetramethylene ammonium bromide (7 g, 1.2eq), and reacting at 0 deg.C for crystallization. Filtration and drying gave g ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dipentyltetramethyleneammonium salt) (yield 76%).
1 H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.88–3.78(m,4H),3.48–3.39(m,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.36–2.26(m,4H),2.16(s,1H),1.93–1.84(m,1H),1.76–1.65(m,4H),1.38–1.28(m,8H),0.95–0.85(m,6H).
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - 264.0298 3g of ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1]-oct-6-yl]Oxy } sulfonyl) (1, 1-dihexyl cyclotetramethylene ammonium salt) is dissolved in absolute ethyl alcohol, an ethanol solution of sodium isooctanoate is dripped under the condition of room temperature, reaction is carried out for 3 hours after dripping is finished, and white solid is obtained, filtered, dried and detected by HPLC. (yield: 89%, purity: 99.90%)
1HNMR(500MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - :264.0298
Example 6
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5g, 18.2mmol), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was carried out at 25 ℃ until completion. Filtering to remove palladium carbon, washing filter cake with water, removing isopropanol by rotary evaporation at 45 deg.C, adding 1, 1-dipentyl cyclohexylammonium bromide (7g, 1.2eq), and reacting at 0 deg.C for crystallization for 3h. Filtration and drying gave 7.7g ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] -oct-6-yl ] oxy } sulfonyl) (1, 1-dipentylcyclohexanemethylammonium salt) (yield 86%)
1 H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).HRMS Calcd for C 7 H 10 N 3 O 6 S:264.0296；HRMS found[M-H] - 264.0298 3g of ({ [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1 { ] -]-oct-6-yl]Oxy } sulfonyl) (1, 1-dipentyl cyclohexylammonium salt) is dissolved in absolute ethyl alcohol, an ethanol solution of sodium isooctanoate is dripped under the condition of room temperature, after the dripping is finished, reaction is carried out for 3 hours to obtain a white solid, and the white solid is filtered, dried and detected by HPLC. (yield 92%, purity 99.94%)
Example 6
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5g, 18.2mmol), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring at room temperature until completion. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, and the filtrate was washed once with 25ml of ethyl acetate (25 ml), followed by addition of 1, 1-dipentylcyclohexylmethyleneammonium bromide (7 g, 1.2eq) and reaction at 40 ℃ for 2 hours. Extracting with dichloromethane (25 ml × 2), combining organic phases, rotary evaporating, adding ethanol and ethyl acetate (3) solvent, crystallizing at 5 ℃, filtering, washing and drying to obtain 5.8g of the avibactam intermediate compound (the yield in the step is 63%).
Weighing 5g of quaternary ammonium sulfonate salt, dissolving the quaternary ammonium sulfonate salt in ethanol (25 ml), dropwise adding ethanol solution of sodium isooctanoate (3.3g, 2eq) into the ethanol solution of the quaternary ammonium sulfonate salt, reacting to precipitate white solid, filtering and drying to obtain 2.4g of avibactam sodium (yield is 87%).
Example 7
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was completed at 30 ℃. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, and the filtrate was washed once with 25ml of ethyl acetate, followed by addition of 80% 1, 1-dipentylcyclohexylmethyleneammonium bromide (5.6 g) and reaction at 40 ℃ for 2 hours. Extraction with dichloromethane (25 ml. Times.2) was carried out, then the remaining 20% of 1, 1-dipentylcyclohexylmethyleneammonium bromide (1.4 g) was added and reacted at 40 ℃ for 2h, extraction with dichloromethane (25 ml. Times.2) was carried out, the organic phases were combined and rotary evaporated, ethanol and ethyl acetate solvent were added for crystallization at 5 ℃, filtration, washing and drying to obtain 5.56g of avibactam intermediate compound (yield 60%). Weighing 5g of quaternary ammonium salt, dissolving the quaternary ammonium salt in ethanol (25 ml), dropwise adding an ethanol solution of sodium isooctanoate (3.3 g, 2eq) into an ethanol solution of quaternary ammonium sulfonate, precipitating a white solid, filtering and drying to obtain 2.5g of abamectin sodium (yield 88%).
Example 8
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was completed at 30 ℃. The palladium on carbon was removed by suction filtration and the filter cake was washed with water, and the filtrate was washed once with 25ml of ethyl acetate, followed by addition of 1, 1-dibutylcyclohexaneammonium bromide (8.7g, 1.5eq) and reaction at 40 ℃ for 2 hours. Extracting with dichloromethane (25 ml × 2), combining organic phases, rotary evaporating, adding ethanol and ethyl acetate solvent, crystallizing at 5 deg.C, filtering, washing and drying to obtain 5.67g of avibactam intermediate compound (yield 62%).
Weighing 5g of quaternary ammonium salt, dissolving the quaternary ammonium salt in ethanol (25 ml), dropwise adding an ethanol solution of sodium isooctanoate (3.3 g, 2eq) into an ethanol solution of quaternary ammonium sulfonate, precipitating a white solid, filtering and drying to obtain 2.43g of abamectin sodium (yield 86%).
Example 9
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was completed at 30 ℃. Removing palladium carbon by suction filtration, washing filter cakes by water, washing filtrate once by 25ml of ethyl acetate, then adding 60 percent of 1, 1-dipentyl cyclohexylammonium bromide (4.2 g) and keeping the temperature at 40 ℃ for reaction for 2 hours, and extracting by dichloromethane (25 ml multiplied by 2); water (12 ml) and isopropanol (12 ml) were added thereto, and the remaining 40% of 1, 1-dipentylcyclohexylideneammonium bromide (2.8 g) was added thereto and the mixture was reacted at 40 ℃ for 2 hours, followed by extraction with methylene chloride (25 ml. Times.2). The combined organic phases are evaporated in a rotary manner, ethanol and ethyl acetate solvent are added for crystallization at the temperature of 5 ℃, and then the avibactam intermediate compound (6.3 g) is obtained after filtration, washing and drying (yield is 68%).
Weighing 5g of quaternary ammonium sulfonate, dissolving the quaternary ammonium sulfonate in ethanol (25 ml), dropwise adding an ethanol solution of sodium isooctanoate (3.3g, 2eq) into the ethanol solution of the quaternary ammonium sulfonate, precipitating white solid, filtering and drying to obtain 2.5g of avibactam sodium (yield 88%).
Example 10
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (5 g,), palladium on carbon (125mg, 10% palladium), sulfur trioxide trimethylamine complex (2.78g, 1.12eq), triethylamine (0.5ml, 0.2eq), isopropanol (25 ml) and water (25 ml) were sequentially added to a 100ml reaction flask, and hydrogen gas was introduced under stirring and the reaction was completed at 30 ℃. Removing palladium carbon by suction filtration, washing a filter cake by water, washing a filtrate once by 25ml of ethyl acetate, adding 60% of 1, 1-dipentyl cyclohexylammonium bromide (4.2 g) and reacting for 2 hours under the condition of keeping 40 ℃, and extracting by dichloromethane (25 ml multiplied by 2); water (12 ml) and isopropanol (12 ml) were added thereto, and the remaining 40% of 1, 1-dipentylcyclohexylideneammonium bromide (2.8 g) was added thereto and the mixture was reacted at 40 ℃ for 2 hours, followed by extraction with methylene chloride (25 ml. Times.2). The combined organic phases were evaporated by rotation, ethanol (30 ml) was added to dissolve, then an ethanol solution of sodium isooctanoate (3.3 g, 2eq) was added dropwise, a white solid precipitated, filtered and dried to obtain 3.17g of abamectin sodium (61% yield in two steps).
Claims (6)
1. Ammonium sulfonate compounds, to compounds of formula (I):
2. a process for preparing a compound according to claim 1, comprising the steps of:
(1) Dissolving (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, sulfur trioxide trimethylamine and triethylamine in alcohol and water, adding a catalyst, introducing hydrogen to remove benzyl, and then performing sulfonation reaction with a sulfonation reagent;
(2) The method a comprises the following steps: completely reacting, filtering to remove palladium carbon, removing alcohol by rotary evaporation, adding a solvent, (2S, 5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide and quaternary ammonium bromide to react and crystallize;
the method b: ethyl acetate washing once, (2S, 5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide reacts with 60% of the total mass of the quaternary ammonium salt, and the product is extracted by dichloromethane; then adding water and isopropanol, adding 40% of the total mass of quaternary ammonium salt for continuous reaction, extracting with dichloromethane, combining the two extraction liquids, performing rotary evaporation, and adding a solvent for crystallization;
(3) After the reaction is finished, the quaternary ammonium sulfonate compound shown in the formula (I) is obtained by suction filtration and drying.
3. The method of claim 2, wherein: in the step (1), the molar ratio of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, sulfur trioxide trimethylamine, triethylamine is 1:1.12:0.2, the catalyst is palladium-carbon containing 10 percent of palladium and 50 percent of water content, the dosage of the catalyst is 0.025 times of the mass of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, the reaction temperature is between 20 and 35 ℃, the reaction time is between 1 and 8 hours, and the reaction solvent is selected from methanol-water, ethanol-water or isopropanol-water mixed solvent.
4. The method of claim 2, wherein: in the method a in the step (2), the rotary evaporation temperature is 25-60 ℃, the molar ratio of (2S, 5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide to quaternary ammonium bromide is 1 (1-1.3), the added amount of the solvent is 1 to 15 percent of the volume of the residual solvent except alcohol, the solvent is selected from acetonitrile, 1, 4-dioxane, acetone, tetrahydrofuran and water, the reaction crystallization temperature is-5 to 10 ℃, and the reaction crystallization time is 1 to 5 hours.
5. The method for preparing a quaternary ammonium sulfonate compound according to claim 2, wherein: in the method b of the step (2), the amount of ethyl acetate is 5 times of the mass of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, the amounts of water and isopropanol added are 2.4 times of the mass of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, respectively, and the reaction crystallization solvent is selected from ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, and acetonitrile-ethyl acetate.
6. The use of the compound of claim 1 in the production of avibactam sodium bulk drug, characterized in that: dissolving 1 molar equivalent of sulfonic acid quaternary ammonium salt in ethanol, dropwise adding 2 molar equivalent of ethanol solution of sodium isooctanoate into the ethanol solution of sulfonic acid quaternary ammonium salt to separate out white solid, filtering and drying to obtain the avibactam sodium.
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