CN102786536B - Sulbactam amoxicillin amide complex for treatment of acute bacterial infection of pig and synthesis method - Google Patents
Sulbactam amoxicillin amide complex for treatment of acute bacterial infection of pig and synthesis method Download PDFInfo
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- CN102786536B CN102786536B CN201210290947.1A CN201210290947A CN102786536B CN 102786536 B CN102786536 B CN 102786536B CN 201210290947 A CN201210290947 A CN 201210290947A CN 102786536 B CN102786536 B CN 102786536B
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- sulbactam
- amoxicillin
- amoxycilline trihydrate
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Abstract
The invention relates to a synthesis method of a sulbactam amoxicillin amide complex, including the following steps: (1) in a solvent, adding the sulbactam with molar weight 1-2 times of amoxicillin, N-hydroxy succinimide with molar weight 2-3 times of the amoxicillin, and dicyclohexylcarbodimide with molar weight 2-5 times of the amoxicillin, filling the nitrogen for protection, adding the amoxicillin in batches for reaction under stirring, slowly pouring reactant into ice water after reaction under stirring, crystallizing, sucking and filtering, washing filter cakes by using cold water and cold absolute ethyl alcohol, pumping, drying under reduced pressure, obtaining white powder-like solid crude product; (2) adding the crude product in the absolute ethyl alcohol in batches under stirring, cooling by using water bath to the room temperature after fully dissolving, precipitating needle-like crystal; then cooling by using cryohydrate bath, keeping warm and sucking and filtering, washing the filter cakes by using a little of cold absolute ethyl alcohol, pumping, drying under reduced pressure, and obtaining the sulbactam amoxicillin amide complex end product. The sulbactam amoxicillin amide complex can be applied in treatment of diseases caused by acute bacterial infection of pigs.
Description
Technical field
The present invention relates to the synthetic of a kind of Sulbactam amoxycilline Trihydrate bp acid amides mixture with treatment pig acute bacterial infections, belong to the synthetic field of medicine.
Background technology
Amoxycilline Trihydrate bp (amoxicillin, amoxycillin, II), for widely used acidproof penbritin class microbiotic, chemical name is (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-p-hydroxybenzene) kharophen]-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-formic acid trihydrate.Amoxycilline Trihydrate bp has a broad antifungal spectrum, sterilizing power are strong, effect rapidly, because its Orally-administrable is widely used in clinical.Can be used for treating typhoid fever, other Salmonella infections, typhoid carrier, the infection of urethra, ear, nose, larynx, respiratory tract and soft tissue.WHO recommends it as first-selected beta-lactam oral antibiotic, has become one of kind noticeable, the most with fastest developing speed in microbiotic kind.Reference is shown in " progress of amoxycilline Trihydrate bp different dosage form [J] ", Sun Wenhua, northwest pharmaceutical journal, the 22nd the 4th phase of volume, 220th～221 pages, in August, 2007.
Sulbactam (Sulbactam, III), chemistry (2S-cis)-3 by name, 3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4,4-dioxide.It is a kind of semisynthetic wide spectrum beta-lactamase inhibitor, and it has very strong irreversible restraining effect to β-lactamase; Share with β-lactam antibitics, there is obvious synergy, in recent years, be pharmaceutically widely used.Reference is shown in " beta-lactamase inhibitor progress [J] ", Gu Juefen, anti-infective pharmacy, the 1st phase in 2004,10th～13 pages, in April, 2004.
Amoxycilline Trihydrate bp/Sulbactam is the compound preparation of amoxycilline Trihydrate bp and Sulbactam.Have at present two kinds of formulations, a kind of is the compound preparation that Amoxicillin Sodium and sulbactam form with 2:1 potency ratio, clinically injection medicine; The compound preparation that amoxycilline Trihydrate bp and Sulbactam ester form with 1:1 potency ratio, clinically pro ore medicine.Amoxycilline Trihydrate bp is combined and is made after compound preparation with Sulbactam, because Sulbactam can protect amoxycilline Trihydrate bp not by beta-lactam enzyme-deactivating, thus the effect that has improved amoxycilline Trihydrate bp anti-product enzyme resistant organism.After two medicine associatings, can expand antimicrobial spectrum, strengthen anti-microbial activity.
In the chemical structure of organic drug is modified, the modification of salify, one-tenth ester and acid amides is the conventional method of a class.This class methods utilization has two kinds of different pharmaceutical molecules of synergetic property function, after using these methods to modify, by the structure amalgamation of two kinds of medicines in a molecule, or by both pharmacophoric group compatibilities in a molecule, be that current medicine worker studies one of interest.Part is modified rear medicine to a certain extent, can strengthen pharmacological action, reduces corresponding toxic side effect separately; Or both are learnt from other's strong points to offset one's weaknesses, performance pharmacologically active separately, synergistically completed treatment process; And after modifying, be more convenient for expanding preparation preparation and route of administration.
Summary of the invention
Technical problem to be solved by this invention be exactly Sulbactam based on having reported and amoxycilline Trihydrate bp compound for basis, a kind of synthetic method for the treatment of the Sulbactam amoxycilline Trihydrate bp acid amides mixture of pig acute bacterial infections is provided.
The structure formula I of the Sulbactam amoxycilline Trihydrate bp acid amides mixture for the treatment of pig acute bacterial infections is:
The synthetic route of above-mentioned Sulbactam amoxycilline Trihydrate bp acid amides mixture is:
In above formula, molecular structure formula II is amoxycilline Trihydrate bp, and molecular structure formula III is Sulbactam.
Technical scheme of the present invention is as follows:
The synthetic method of Sulbactam amoxycilline Trihydrate bp acid amides mixture comprises the following steps:
(1) in solvent, add the Sulbactam (III) of 1-2 times of molar weight of amoxycilline Trihydrate bp (II), the dicyclohexylcarbodiimide (DCC) of the N-hydroxy-succinamide (NHS) of 2-3 times molar weight, 2-5 times molar weight, inflated with nitrogen protection, under stirring, add amoxycilline Trihydrate bp (II) to react in batches, under the complete stirring of reaction, reactant is slowly poured in frozen water, crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively, drain, drying under reduced pressure, obtains white powder solid crude product (I);
(2) crude product (I) under agitation adds in dehydrated alcohol in batches, and after all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal; Cooling with cryosel bath again, insulation, suction filtration, a small amount of cold absolute ethanol washing for filter cake, drains, and drying under reduced pressure obtains Sulbactam amoxycilline Trihydrate bp acid amides mixture (I) finished product.
Solvent in step (1) is ethyl acetate, tetrahydrofuran (THF), dioxane or the wherein mixing of two kinds of solvents.
Temperature of reaction in step (1) is 5 ℃ to 30 ℃, and the reaction times is 5 to 24 hours.
Dehydrated alcohol temperature in step (2) is 50 ℃ to 80 ℃.
It is 0 ℃ to subzero 15 ℃ that cryosel in step (2) is bathed cooling temperature, and soaking time is 1 to 3 hour.
Sulbactam amoxycilline Trihydrate bp acid amides mixture can be treated light, the moderate acute bacterial infections of the caused respiratory system of pig acute bacterial infections, urinary system etc.
Embodiment
Design of the present invention is: under the condition of cyclohexyl charcoal acyl two sub-acid amides (DCC) and N-hydroxy-succinamide (NHS) existence, acylation reaction is carried out in Sulbactam and amoxycilline Trihydrate bp, obtains acid amides mixture.
Below in conjunction with embodiment, the invention will be further described:
Embodiment 1: measure 100mL ethyl acetate; the Sulbactam, 3mmol N-hydroxy-succinamide (NHS), the 3mmol dicyclohexylcarbodiimide (DCC) that add 1mmol molar weight; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 5 ℃ of temperature, stir 24 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 50 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to subzero 15 ℃ again, be incubated 3 hours.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 83%, white powder solid.mp138.8-139.4℃，ESI-MS(m/z):603.64[M+Na]
Embodiment 2: measure 150mL dioxane; the Sulbactam, 2mmol N-hydroxy-succinamide (NHS), the 2mmol dicyclohexylcarbodiimide (DCC) that add 2mmol molar weight; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 30 ℃ of temperature, stir 5 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 60 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to 0 ℃ again, be incubated 1 hour.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 79.6%, white powder solid.mp138.1-139.0℃，ESI-MS(m/z):603.66[M+Na]
Embodiment 3: measure 100mL tetrahydrofuran (THF) and dioxane (1:1) mixed solvent; the Sulbactam, 3mmol N-hydroxy-succinamide (NHS), the 5mmol dicyclohexylcarbodiimide (DCC) that add 1.5mmol; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 20 ℃ of temperature, stir 12 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 80 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to subzero 10 ℃ again, be incubated 3 hours.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 88.1%, white powder solid.mp138.5-139.4℃，ESI-MS(m/z):603.48[M+Na]
Embodiment 4: measure 100mL tetrahydrofuran (THF) and dioxane (2:1) mixed solvent; the Sulbactam, 3mmol N-hydroxy-succinamide (NHS), the 5mmol dicyclohexylcarbodiimide (DCC) that add 1.5mmol; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 30 ℃ of temperature, stir 12 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 70 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to subzero 15 ℃ again, be incubated 2 hours.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 85.1%, white powder solid.mp138.1-139.2℃，ESI-MS(m/z):603.44[M+Na]
Embodiment 5: measure 100mL tetrahydrofuran (THF); the Sulbactam, 3mmol N-hydroxy-succinamide (NHS), the 3mmol dicyclohexylcarbodiimide (DCC) that add 1.5mmol; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 25 ℃ of temperature, stir 20 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 50 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to subzero 10 ℃ again, be incubated 3 hours.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 87.5%, white powder solid.mp138.8-139.6℃，ESI-MS(m/z):603.38[M+Na]
Embodiment 6: measure 150mL ethyl acetate and dioxane (1:2) mixed solvent; the Sulbactam, 2mmol N-hydroxy-succinamide (NHS), the 2mmol dicyclohexylcarbodiimide (DCC) that add 2mmol; inflated with nitrogen protection; under stirring, add 1mmol amoxycilline Trihydrate bp in batches, at 30 ℃ of temperature, stir 24 hours; under the complete stirring of reaction, reactant is slowly poured in frozen water; crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively.Drain, drying under reduced pressure, obtains white powder solid crude product.
Crude product adds in the dehydrated alcohol of 65 ℃ under stirring in batches.After all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal.With cryosel, bathe and be cooled to subzero 15 ℃ again, be incubated 2.5 hours.Suction filtration, a small amount of cold absolute ethanol washing 2 times for filter cake, after draining, drying under reduced pressure, (I) finished product be title product Sulbactam amoxycilline Trihydrate bp acid amides mixture.Productive rate 89.02%, white powder solid.mp138.15-139.09℃，ESI-MS(m/z):603.33[M+Na]
Experiment 1: Sulbactam amoxycilline Trihydrate bp acid amides mixture and Sulbactam/amoxycilline Trihydrate bp (1/1) evaluation of clinical curative effect result to piglet acute bacterial infections:
Whole tested case pigs be in clinical and laboratory is really precious, severe acute bacterium infects.Treatment group 150 examples, respiratory system infection 105 examples, other system infects 45 examples; The state of an illness belongs to moderate 125 examples, severe 25 examples; Positive rate of bacteria 83% (125/150).Control group 130 examples, respiratory system infection 90 examples, other system infects 40 examples; The state of an illness belongs to moderate 105 examples, severe 25 examples; Positive rate of bacteria 92% (120/130).Two groups of March at age, 50 ± 5 kilograms of body weight, severity extent etc. all have comparability.
Every bottle of powder injection containing 1.5 grams of Sulbactam amoxycilline Trihydrate bp acid amides mixtures for treatment group, every bottle of powder injection containing 1.5 grams of amoxycilline Trihydrate bp/Sulbactams (1/1) for control group, two groups all dissolve with injection water, all by 15 milligrams of injections of per kilogram of body weight, subcutaneous injection, 3 days courses for the treatment of.
Two groups of clinical efficacies and bacteriology curative effect relatively see the following form:
| Index | Treatment group | Control group |
| Number of cases (example) | 150 | 130 |
| Recovery from illness (example) | 105 | 65 |
| Effective (example) | 35 | 30 |
| Progressive (example) | 10 | 25 |
| Invalid (example) | 0 | 10 |
| Cure rate (%) | 70 | 50 |
| Efficient (%) | 93 | 73 |
| Bacterial strain number (strain) | 26 | 24 |
| Produce enzyme strain number (strain) | 35 | 60 |
| Remove (example) | 120 | 100 |
| Do not remove (example) | 5 | 15 |
| Replace (example) | 5 | 5 |
| Clearance rate (%) | 92 | 83 |
Note: clinical efficacy is evaluated by level Four: (1) recovery from illness: symptom, sign, laboratory are sent out etiological examination and all recovered normal; (2) effective: the state of an illness is clearly better, but in above four, have one not recover normal completely; (3) progressive: the state of an illness take a favorable turn, but obvious not; (4) invalid: after medication, 72 hours state of an illness are without taking a turn for the better or adding severe one.Recovery from illness is recorded as effectively with effective, and calculates accordingly efficient.
Bacteriological evaluation is by following standard rating: remove (1): finish rear microbial culture the course for the treatment of and grow without pathogenic bacterium; (2) part is removed: a kind of removing in two or more pathogenic bacterium of former cultivation; (3) do not remove: finish rear former pathogenic bacterium the course for the treatment of and still exist; (4) replace: finish rear former pathogenic bacterium the course for the treatment of and remove, but cultivate the pathogenic bacterium that make new advances, without infecting clinical manifestation, without treating; (4) infect again: through treating original bacterium, remove, infect once again other bacterium and need to treat.
Experiment 2: antibacterial activity in vitro evaluation
The demonstration of paper disk method drug sensitive test result, 50 strain pathogenic bacterium are up to 98% and 90% to the responsive rate of Sulbactam amoxycilline Trihydrate bp acid amides mixture and amoxycilline Trihydrate bp/Sulbactam (1/1), and secondly ceftiofur is 82%.Amoxicillin/clavulanate is 78%, and amoxycilline Trihydrate bp is 62%, and Cephradine is minimum is 48%.The antibacterial activity in vitro that shows Sulbactam amoxycilline Trihydrate bp acid amides mixture is all more superior than amoxycilline Trihydrate bp/Sulbactam (1/1), amoxycilline Trihydrate bp etc.
In sum, Sulbactam amoxycilline Trihydrate bp acid amides mixture is used for the treatment of in the blue male part bacterium of leather and negative microbial pig, severe infection, and especially, to the infection determined curative effect being caused by zymogenic bacteria, clinic is applied.
Claims (5)
1. a synthetic method for Sulbactam amoxycilline Trihydrate bp acid amides mixture, is characterized in that this synthetic method comprises the following steps:
(1) in solvent, add the Sulbactam (III) of 1-2 times of molar weight of amoxycilline Trihydrate bp (II), the dicyclohexylcarbodiimide (DCC) of the N-hydroxy-succinamide (NHS) of 2-3 times molar weight, 2-5 times molar weight, inflated with nitrogen protection, under stirring, add amoxycilline Trihydrate bp (II) to react in batches, under the complete stirring of reaction, reactant is slowly poured in frozen water, crystallization, suction filtration, filter cake is used cold water and cold absolute ethanol washing successively, drain, drying under reduced pressure, obtains white powder solid crude product (I);
(2) crude product (I) under agitation adds in dehydrated alcohol in batches, and after all dissolving, water-bath is cooled to room temperature, separates out needle-like crystal; Cooling with cryosel bath again, insulation, suction filtration, a small amount of cold absolute ethanol washing for filter cake, drains, and drying under reduced pressure obtains Sulbactam amoxycilline Trihydrate bp acid amides mixture (I) finished product.
2. the synthetic method of Sulbactam according to claim 1 amoxycilline Trihydrate bp acid amides mixture, is characterized in that: the solvent in step (1) is ethyl acetate, tetrahydrofuran (THF), dioxane or the wherein mixing of two kinds of solvents.
3. the synthetic method of Sulbactam according to claim 2 amoxycilline Trihydrate bp acid amides mixture, is characterized in that: the temperature of reaction in step (1) is 5 ℃ to 30 ℃, and the reaction times is 5 to 24 hours.
4. the synthetic method of Sulbactam according to claim 3 amoxycilline Trihydrate bp acid amides mixture, is characterized in that: the dehydrated alcohol temperature in step (2) is 50 ℃ to 80 ℃.
5. the synthetic method of Sulbactam according to claim 4 amoxycilline Trihydrate bp acid amides mixture, is characterized in that: it is 0 ℃ to subzero 15 ℃ that cryosel is bathed cooling temperature, and soaking time is 1 to 3 hour.
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