CN112724162A - Synthesis method and application of amoxicillin-sulbactam hybrid molecule - Google Patents
Synthesis method and application of amoxicillin-sulbactam hybrid molecule Download PDFInfo
- Publication number
- CN112724162A CN112724162A CN202011584840.9A CN202011584840A CN112724162A CN 112724162 A CN112724162 A CN 112724162A CN 202011584840 A CN202011584840 A CN 202011584840A CN 112724162 A CN112724162 A CN 112724162A
- Authority
- CN
- China
- Prior art keywords
- sulbactam
- amoxicillin
- solution
- hybrid molecule
- stirring
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/08—Modification of a carboxyl radical directly attached in position 2, e.g. esterification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis method and application of an amoxicillin-sulbactam heterozygous molecule, belonging to the technical field of organic synthesis. The yield of a key intermediate, namely sulbactam chloromethyl is effectively improved by taking chlorobromomethane as a chloromethyl reagent of sulbactam acid, and the amoxicillin-sulbactam heterozygous molecule is prepared by taking sulbactam chloromethyl and (Z) -6- (2- (4-hydroxyphenyl) -2- ((4-methoxy-4-oxobut-2-en-2-yl) amino) acetamido) -3, 3-dimethyl-7-oxo-4-sulfur-1-azabicyclo [3.2.0] heptane-2-carboxylic acid as raw materials, carrying out condensation reaction and removing a protecting group by using strong acid. The synthesis method has the advantages of mild reaction conditions, cheap and easily-obtained raw materials, low preparation cost, good safety, simple and easy process and high product yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method and application of an amoxicillin-sulbactam hybrid molecule.
Background
The amoxicillin-sulbactam hybrid molecule is an analogue of antibacterial sulbactam, is a diester structure compound formed by connecting amoxicillin and sulbactam acid by methylene bridge, and has the following chemical structure:
the B lactam antibiotic (amoxicillin) and the B lactamase inhibitor (sulbactam) are combined, so that the antibacterial activity of the amoxicillin on drug-resistant bacteria is improved, and the application prospect is good.
US4380512 reports a synthesis method of amoxicillin-sulbactam hybrid molecule, which has complex operation, harsh reaction conditions and low yield (less than 10%). In recent years, no literature is available for updating and improving the synthesis method of the amoxicillin-sulbactam hybrid molecule, so that a new synthesis method of the amoxicillin-sulbactam hybrid molecule is needed to be explored, a new synthesis process which is cheap, efficient, simple and convenient to operate and suitable for industrial production is developed, and the application and development of the amoxicillin series hybrid molecule are greatly promoted.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a synthesis method of an amoxicillin-sulbactam hybrid molecule, which can effectively improve the yield of a key intermediate, namely sulbactam chloromethyl ester, thereby improving the product yield.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a synthetic method of an amoxicillin-sulbactam hybrid molecule comprises the following synthetic route:
the method specifically comprises the following steps:
s1, taking sulbactam acid as a raw material, and reacting the sulbactam acid with tetrabutylammonium hydrogen sulfate in water to form salt to obtain an intermediate 1;
s2, carrying out substitution reaction on the intermediate 1 prepared in the step S1 and bromochloromethane in the presence of pyridine to prepare an intermediate 2;
s3, iodinating the intermediate 2 prepared in the step S2 in an organic solvent through NaI to obtain an intermediate 3;
s4, taking amoxicillin trihydrate as a raw material, and carrying out dehydration condensation on the amoxicillin trihydrate and methyl acetoacetate in an organic solution to obtain an intermediate 4;
s5, carrying out substitution reaction on the intermediate 3 prepared in the step S3 and the intermediate 4 prepared in the step S4 in the presence of potassium carbonate to obtain an intermediate 5;
s6, placing the intermediate 5 prepared in the step S5 in an acetone aqueous solution, and removing side chains on amino groups through strong acid to obtain the amoxicillin-sulbactam hybrid molecule.
As a preferred embodiment of the present invention, the step S1 specifically includes the following steps:
s11, taking sulbactam acid as a raw material, and reacting with tetrabutylammonium hydrogen sulfate at room temperature;
s12, adding alkali to adjust the pH value to be neutral, adding dichloromethane and stirring;
s13, extracting, separating, collecting an organic layer, dehydrating by using anhydrous sodium sulfate, and performing reduced pressure rotary evaporation to remove the solvent to obtain an intermediate 1.
Preferably, the molar equivalent of tetrabutylammonium hydrogen sulfate in the step S11 is 2.0-2.5. The alkali in the step S12 is NaOH.
As a preferred embodiment of the present invention, the S2 specifically includes the following steps:
s21, dissolving the intermediate 1 prepared in the step S1 in bromochloromethane containing pyridine, and stirring at room temperature in a dark place for 3.5-4.5 h;
s22, the reaction mixture of step S21 is washed with water, a saturated sodium sulfate solution and saturated brine in this order, and the organic layer is collected and dried over anhydrous magnesium sulfate to obtain intermediate 2.
Preferably, in the step S21, the molar equivalent of pyridine is 0.5-1.5, and the molar equivalent of chlorobromomethane is 200-300.
As a preferred embodiment of the present invention, the step S3 specifically includes the following steps:
s31, dissolving the intermediate 2 obtained in the step S2 in an organic solvent, adding NaI with the molar equivalent of 1.5-5 for iodination, and stirring at room temperature in a dark place for 5-16 hours; the organic solvent is one or a mixture of more than two of dichloromethane, acetone and ethyl acetate;
s32, after the reaction is finished, reducing the temperature of the solution to 0-5 ℃, keeping stirring, adjusting the pH to 3.0-7.3 by using saturated sodium bicarbonate, and then dropwise adding 1-5 mol/L sodium thiosulfate solution to decolorize the solution;
and S33, adding water with the same volume as the organic solvent, continuously stirring until white crystals are separated out, filtering and collecting filter residues, and performing vacuum drying at 25-50 ℃ to obtain an intermediate 3.
Preferably, the organic solvent in step S31 is one or a mixture of any two or more of dichloromethane, acetone and ethyl acetate.
As a preferred embodiment of the present invention, the step S4 specifically includes the following steps:
s41, suspending alkali in an organic solvent, adding methyl acetoacetate and amoxicillin trihydrate, and stirring at room temperature for 1-6 h;
s42, filtering to remove the organic solvent, washing filter residues twice with diethyl ether, and performing vacuum drying at 30-50 ℃ to obtain an intermediate 4.
Preferably, the organic solvent in step S41 is one of N, N-dimethylformamide, chloroform and N, N-dimethyl sulfoxide, and the added base is one of potassium carbonate, sodium carbonate and sodium bicarbonate.
As a preferred embodiment of the present invention, the step S5 specifically includes the following steps:
s51, dissolving the intermediate 4 obtained in the step S4 in an organic solvent, reducing the temperature of the solution to 5-10 ℃, adding the intermediate 3 obtained in the step S3 in batches, and stirring for 2-8 hours;
s52, after the reaction is finished, pouring the solution into a mixed solution of ethyl acetate and saturated calcium chloride, extracting and layering, collecting an organic layer, washing the organic layer with a saturated calcium chloride solution at 25 ℃, adding diatomite for filtering, concentrating the filtrate under reduced pressure, and drying in vacuum to obtain an intermediate 5.
Preferably, the organic solvent in step S51 is one of N, N-dimethylformamide, chloroform, and N, N-dimethyl sulfoxide; the mixing volume ratio in the mixed solution of the step S52 is ethyl acetate: the saturated calcium chloride solution is 1: 1-3: 1.
As a preferred embodiment of the present invention, the step S6 specifically includes the following steps:
s61, dissolving the intermediate 5 obtained in the step S5 in a mixed solution, reducing the temperature of the solution to 0-5 ℃, adding strong acid, stirring and continuously monitoring the pH value of the system to be stable at 1.0-4.0;
s62, evaporating the organic solvent under reduced pressure, adding excessive NaCl into the residual solution, adding an ethyl acetate-acetone mixed solution for extraction and layering, collecting an organic layer, removing water through anhydrous sodium sulfate, and then performing reduced pressure spin drying to obtain an amoxicillin-sulbactam heterozygous molecule;
preferably, the mixed solution of step S61 is an acetone aqueous solution, wherein the volume ratio of acetone to water is 1: 2-3: 1; the strong acid in the step S61 is hydrochloric acid or p-methoxybenzenesulfonic acid, and the concentration is 1-2 mol/L; the volume ratio of ethyl acetate to acetone in the mixed solution of the step S62 is 1: 1-4: 1.
the invention also provides an antibacterial active composition containing the amoxicillin-sulbactam hybrid molecule prepared by the method, wherein the content of the amoxicillin-sulbactam hybrid molecule in the composition is 0.1-99.5 wt%, and the balance is pharmaceutic adjuvant.
Preferably, the pharmaceutic adjuvant is one or a mixture of more than two of polyvinylpyrrolidone K30, poloxamer 188, tween 80, span or starch.
Preferably, the dosage form of the antibacterial active composition is oral preparation or injection.
Compared with the prior art, the invention has the beneficial effects that:
the raw materials and reagents used in the preparation method provided by the invention are low in price and easy to obtain commercially, and the yield of the key intermediate sulbactam chloromethyl ester is effectively improved by taking the chlorobromomethane as the chloromethyl reagent of sulbactam acid, so that the overall product yield is improved. The invention improves the synthesis method of the amoxicillin-sulbactam heterozygote molecule, has simple and easy process, low requirement on experimental equipment, mild reaction condition and good safety, and can obviously improve the total yield, and has good industrial application prospect, and the total yield can reach 70-80%.
Detailed Description
The method of the present invention is described below with reference to specific examples to make it easier to understand and understand the technical solution of the present invention, but the present invention is not limited thereto. The experimental procedures described in the following examples are, unless otherwise specified, conventional: the reagents and materials are commercially available, unless otherwise specified.
A synthetic method of an amoxicillin-sulbactam hybrid molecule comprises the following synthetic route:
the method specifically comprises the following steps:
s1, preparing an intermediate 1, which comprises the following steps:
s11, taking sulbactam acid as a raw material, and reacting with tetrabutylammonium hydrogen sulfate at room temperature;
s12, adding alkali to adjust the pH value to be neutral, adding dichloromethane and stirring;
s13, extracting, separating, collecting an organic layer, dehydrating by using anhydrous sodium sulfate, and performing reduced pressure rotary evaporation to remove the solvent to obtain an intermediate 1.
S2, preparing an intermediate 2, which comprises the following steps:
s21, dissolving the intermediate 1 prepared in the step S1 in bromochloromethane containing pyridine, and stirring at room temperature in a dark place for 3.5-4.5 h;
s22, the reaction mixture of step S21 is washed with water, a saturated sodium sulfate solution and saturated brine in this order, and the organic layer is collected and dried over anhydrous magnesium sulfate to obtain intermediate 2.
S3, preparing an intermediate 3, which comprises the following steps:
s31, dissolving the intermediate 2 obtained in the step S2 in an organic solvent, adding NaI with a molar ratio equivalent of 1.5-5 for iodination, and stirring at room temperature in a dark place for 5-16 h;
s32, after the reaction is finished, reducing the temperature of the solution to 0-5 ℃, keeping stirring, adjusting the pH to 3.0-7.3 by using saturated sodium bicarbonate, and then dropwise adding 1-5 mol/L sodium thiosulfate solution to decolorize the solution;
and S33, adding water with the same volume as the organic solvent, continuously stirring until white crystals are separated out, filtering and collecting filter residues, and performing vacuum drying at 25-50 ℃ to obtain an intermediate 3.
S4, preparing the intermediate 4, which comprises the following steps:
s41, suspending alkali in an organic solvent, adding methyl acetoacetate and amoxicillin trihydrate, and stirring at room temperature for 1-6 h;
s42, filtering to remove the solvent, washing filter residues twice with diethyl ether, and performing vacuum drying at 30-50 ℃ to obtain an intermediate 4.
S5, preparing an intermediate 5, which comprises the following steps:
s51, dissolving the intermediate 4 obtained in the step S4 in an organic solvent, reducing the temperature of the solution to 5-10 ℃, adding the intermediate 3 obtained in the step S3 in batches, and stirring for 2-8 hours;
s52, after the reaction is finished, pouring the solution into a mixed solution of ethyl acetate and saturated calcium chloride, extracting and layering, collecting an organic layer, washing the organic layer with a saturated calcium chloride solution at 25 ℃, adding diatomite for filtering, concentrating the filtrate under reduced pressure, and drying in vacuum to obtain an intermediate 5.
S6, preparing the amoxicillin-sulbactam hybrid molecule, which comprises the following steps:
s61, dissolving the intermediate 5 obtained in the step S5 in a mixed solution, reducing the temperature of the solution to 0-5 ℃, adding strong acid, stirring and continuously monitoring the pH value of the system to be stable at 1.0-4.0;
s62, evaporating the organic solvent in the mixed solution under reduced pressure, adding excessive NaCl into the residual solution, adding an ethyl acetate-acetone mixed solution for extraction and layering, collecting an organic layer, removing water by using anhydrous sodium sulfate, and then carrying out reduced pressure spin drying to obtain the amoxicillin-sulbactam hybrid molecule.
Example 1:
preparation of intermediate 1
Tetrabutylammonium hydrogen sulfate (26.4g, 0.078mol) was dissolved in 100ml of water and stirred at room temperature. After the pH was adjusted to 7(2N NaOH) (20ml), sulbactam sodium (10g, 0.039mol) was added, and the pH of the reaction system was adjusted back to 6.9 with 2N NaOH, 150ml of methylene chloride was added, and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was washed with 150ml of dichloromethane, the organic layers were combined, dried over anhydrous MgSO4 and spin dried to give an oil. Vacuum drying to obtain 20.2g of intermediate 1, yield 92.7% and purity 85.2%.1HNMR(600MHz,Chloroform-d)δ10.82(s,1H),5.66(d,J＝2.8Hz,2H),4.60-4.65(m,1H),4.32(s,1H,),3.45-3.56(dd,J＝6.1,8.3Hz,2H),1.59(s,3H),1.41(s,3H)；
Preparation of intermediate 2
The resulting intermediate 1(20.2g) was dissolved in 460mL of chlorobromomethane containing 3mL of pyridine (0.039mol), stirred at room temperature in the dark for 3.5h, and the reaction mixture was washed with a separatory funnel in the following order: 300ml of water, 300ml of a saturated sodium sulfate solution and 300ml of a saturated NaCl solution, and the organic phase was collected and concentrated under reduced pressure to obtain 9.76g of intermediate 2 as a pale yellow solid with a yield of 91.3% and a purity of 95.2%.1HNMR(600MHz,Chloroform-d)δ5.64-5.94(dd,J＝8.8,11.2Hz,2H,CH2),4.64-4.66(m,1H),4.42(s,1H,),3.42-3.53(dd,J＝7.1,6.3Hz,2H),1.63(s,3H),1.46(s,3H)；13C NMR(151MHz,Chloroform-d)δ170.72(C＝O),165.47(C＝O),69.39,62.77,62.74,60.96,38.31,21.10,18.33；
Preparation of intermediate 3
The obtained intermediate 2(9.76g, 0.033mol) was dissolved in 100mL of acetone, NaI (4.95g, 0.033mol) was added thereto, and the mixture was stirred at room temperature for 16 hours, after completion of the reaction, the temperature of the system was lowered to 0 to 5 ℃ and the pH of the system was adjusted to neutral with a saturated sodium bicarbonate solution, followed by addition of 1mol/L sodium thiosulfate for decolorization. And finally, adding 100mL of water, keeping the temperature of 0-5 ℃, continuing stirring for 30min, separating out a large amount of white crystals, filtering and collecting a filter cake, washing the filter cake with water, and performing vacuum drying for 6h to obtain 11.7g of white solid, wherein the yield is 94.6%, and the purity is 99.4%.
Preparation of intermediate 4
Suspending anhydrous potassium carbonate (7.6g, 0.055mol) in DMF (150mL), adding amoxicillin trihydrate 25.2g (0.06mol), adding methyl acetoacetate 6.48mL (0.06mol), stirring at room temperature for 2h, cooling the solution to 0-5 ℃, continuing stirring for 4h, filtering the solution, and collecting the filtrate. Adding 250ml of diethyl ether into the filtrate, continuously stirring for 5min at 0-5 ℃, standing for 30min, pouring out the upper layer liquid, adding 100ml of diethyl ether for 2 times until no new precipitate is generated, filtering to remove diethyl ether, washing the filter residue with diethyl ether once, and then drying in vacuum to obtain 22.92g of intermediate 4 which is light yellow solid, wherein the yield is 70.4% and the purity is 85.2%.1HNMR(600MHz,Chloroform-d)δ10.71(s,1H,COOH),9.24(d,J＝6.0Hz,1H,CONH),8.85(d,J＝3.5Hz,1H,),7.14(d,J＝5.1Hz,2H),6.76(d,J＝8.5Hz,2H),5.47(d,J＝8.2Hz,1H),5.38-5.40(m,J＝8.1Hz,1H),5.27(d,J＝4.2Hz,1H),4.45(s,1H),3.88(s,1H),3.52(s,3H),3.41(s,3H),1.76(s,3H),1.56(s,3H),1.42(s,3H)；13C NMR(151MHz,Chloroform-d)δ173.45(C＝O),170.68(C＝O),169.94(C＝O),169.85(C＝O),160.66,158.30,128.93,127.82,127.78,115.99,83.45,74.61,66.92,64.88,58.17,57.50,50.03,31.63,27.96,19.67。
Preparation of intermediate 5
Dissolving the intermediate 4(14.467,0.031mol) in 250ml of DMF, stirring at 5-10 ℃, adding the intermediate 3(11.7g, 0.31mol) in multiple times, keeping the temperature low, continuously stirring for 3.5h, pouring the reaction liquid into a cold mixed solution of 200ml of ethyl acetate and 100ml of saturated calcium chloride after the reaction is finished, and separating an organic layer (extraction). The organic layer was washed with 50ml of saturated calcium chloride and filtered through celite. The filtrate was rotary dried under reduced pressure to give 20.39g of intermediate 5 as a pale yellow solid in 86.3% yield and 92.3% purity.1H NMR(600MHz,Chloroform-d)δ9.75(s,1H),9.26(d,J＝5.6Hz,1H,CONH),8.58(s,2H,),7.27(d,J＝7.1Hz,2H),6.83(d,J＝4.6Hz,2H),5.84-5.88(m,2H),5.51(s,1H),5.25(d,J＝2.1Hz,1H),4.90(s,1H),4.76(s,1H),4.48(s,1H),3.64-3.69(dd,J＝2.4,4.1Hz,1H),3.45(s,3H),3.22(s,1H),1.76(s,3H),1.54(s,3H),1.46(s,3H),1.33(d,J＝7.2Hz,6H)。
Preparation of amoxicillin-sulbactam hybrid molecule
Intermediate 5(20.3g, 0.027mol) was dissolved in 150mL of acetone water (v: v ═ 2:1), reacted at 0-5 ℃, and hydrochloric acid (1mol/L) was added dropwise to adjust the system pH to 2.0, stirring and continuously monitoring that the system pH stabilized at 2.0. 60ml of water was added to the reaction solution, and the acetone was removed by rotary evaporation under reduced pressure, excess NaCl was added to the remaining solution, and 100ml of ethyl acetate-acetone (v: v ═ 2:1) was added to extract the compound, and the aqueous layer was separated and extracted once more with ethyl acetate-acetone (2: 1). The organic layer was collected, dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to remove the solvent, yielding 15.89g of amoxicillin-sulbactam hybrid molecule as a pale yellow solid with a yield of 91.8% and a purity of 95.3%.1H NMR(600MHz,Chloroform-d)δ9.85(s,1H),9.29(d,J＝3.6Hz,1H,CONH),8.63(s,2H,),7.29(d,J＝6.3Hz,2H),6.80(d,J＝7.5Hz,2H),5.89-5.92(m,2H),5.58(s,1H),5.20(d,J＝2.1Hz,1H),4.94(s,1H),4.56(s,1H),3.67-3.71(dd,J＝3.4,2.1Hz,1H),3.28(s,1H),1.52(s,3H),1.48(s,3H),1.36(d,J＝6.5Hz,6H)；13C NMR(151MHz,Chloroform-d)δ176.41(C＝O),172.18(C＝O),171.77(C＝O),169.81(C＝O),167.53(C＝O),146.32,129.94,128.76,127.74,118.90,83.43,80.56,75.71,67.82,65.38,63.29,55.15,53.02,51.13,37.83,28.36,24.76,19.88,18.79,18.64。
Example 2
Preparation of intermediate 1
Tetrabutylammonium hydrogen sulfate (26.4g, 0.0975mol) was dissolved in 100ml of water and stirred at room temperature. After the pH was adjusted to 7(2N NaOH) (20ml), sulbactam sodium (10g, 0.039mol) was added, the pH of the reaction system was adjusted back to 6.9 with 2N NaOH, and then 150ml of dichloromethane was added and stirred for 10 min. The layers were separated and the aqueous layer was washed with 150ml of dichloromethane, the organic layers were combined, dried over anhydrous MgSO4 and spin dried to give an oil. After vacuum drying, 21.25g of intermediate 1 was obtained in 94.8% yield and 82.81% purity.
Preparation of intermediate 2
The resulting intermediate 1(21.25g, 0.037mol) was dissolved in 460mL of chlorobromomethane containing 3mL of pyridine (0.039mol), stirred at room temperature for 3.5h in the absence of light, and the reaction mixture was washed with a separatory funnel in the following order: 300ml of water, 300ml of saturated sodium sulfate solution, 300ml of saturated NaCl solution, the organic phase was collected and concentrated under reduced pressure to give 10.29g of intermediate 2 as a pale yellow solid with a yield of 92.4% and a purity of 93.5%.1HNMR(600MHz,Chloroform-d)δ5.64-5.94(dd,J＝8.8,11.2Hz,2H,CH2),4.64-4.66(m,1H),4.42(s,1H,),3.42-3.53(dd,J＝7.1,6.3Hz,2H),1.63(s,3H),1.46(s,3H)；13C NMR(151MHz,Chloroform-d)δ170.72(C＝O),165.47(C＝O),69.39,62.77,62.74,60.96,38.31,21.10,18.33。
Preparation of intermediate 3
The obtained intermediate 2(10.29, 0.034mol) was dissolved in 100mL of acetone, NaI (4.95g, 0.033mol) was added and stirred at room temperature for 16 hours, and after the reaction was completed, the temperature of the system was lowered to 0-5 ℃ and the pH of the system was adjusted to neutral with a saturated sodium bicarbonate solution, followed by addition of 1mol/L sodium thiosulfate for decolorization. And finally, adding 100mL of water, keeping the temperature of 0-5 ℃, continuously stirring for 30min, separating out a large amount of white crystals, filtering and collecting a filter cake, washing the filter cake with water, and performing vacuum drying for 6h to obtain 12.36g of white solid, wherein the yield is 95.7%, and the purity is 99.4%.
Preparation of intermediate 4
Suspending anhydrous potassium carbonate (7.6g, 0.055mol) in DMF (150mL), adding amoxicillin trihydrate 25.2g (0.06mol), adding methyl acetoacetate 6.48mL (0.06mol), stirring at room temperature for 2h, cooling the solution to 0-5 ℃, continuing stirring for 4h, filtering the solution, and collecting the filtrate. Adding 250ml of diethyl ether into the filtrate, continuously stirring for 5min at 0-5 ℃, standing for 30min, pouring out the upper layer liquid, adding 100ml of diethyl ether for 2 times until no new precipitate is generated, filtering to remove the diethyl ether, washing the filter residue with diethyl ether once, and then drying in vacuum to obtain 26.18g of intermediate 4 which is light yellow solid, the yield is 69.3% and the purity is 86.3%.1HNMR(600MHz,Chloroform-d)δ10.71(s,1H,COOH),9.24(d,J＝6.0Hz,1H,CONH),8.85(d,J＝3.5Hz,1H,),7.14(d,J＝5.1Hz,2H),6.76(d,J＝8.5Hz,2H),5.47(d,J＝8.2Hz,1H),5.38-5.40(m,J＝8.1Hz,1H),5.27(d,J＝4.2Hz,1H),4.45(s,1H),3.88(s,1H),3.52(s,3H),3.41(s,3H),1.76(s,3H),1.56(s,3H),1.42(s,3H)；13C NMR(151MHz,Chloroform-d)δ173.45(C＝O),170.68(C＝O),169.94(C＝O),169.85(C＝O),160.66,158.30,128.93,127.82,127.78,115.99,83.45,74.61,66.92,64.88,58.17,57.50,50.03,31.63,27.96,19.67。
Preparation of intermediate 5
Dissolving the intermediate 4(14.467,0.031mol) in 250ml of DMF, stirring at 5-10 ℃, adding the intermediate 3(11.7g, 0.31mol) in multiple times, keeping the temperature low, continuously stirring for 3.5h, pouring the reaction liquid into a cold mixed solution of 200ml of ethyl acetate and 100ml of saturated calcium chloride after the reaction is finished, and separating an organic layer (extraction). The organic layer was washed with 50ml of saturated calcium chloride and filtered through celite. The filtrate was rotary dried under reduced pressure to give 21.22g of intermediate 5 as a pale yellow solid in 84.15% yield and 93.7% purity.1H NMR(600MHz,Chloroform-d)δ9.75(s,1H),9.26(d,J＝5.6Hz,1H,CONH),8.58(s,2H,),7.27(d,J＝7.1Hz,2H),6.83(d,J＝4.6Hz,2H),5.84-5.88(m,2H),5.51(s,1H),5.25(d,J＝2.1Hz,1H),4.90(s,1H),4.76(s,1H),4.48(s,1H),3.64-3.69(dd,J＝2.4,4.1Hz,1H),3.45(s,3H),3.22(s,1H),1.76(s,3H),1.54(s,3H),1.46(s,3H),1.33(d,J＝7.2Hz,6H)。
Preparation of amoxicillin-sulbactam hybrid molecule
Intermediate 5(21.22g, 0.026mol) was dissolved in 150mL of acetone water (v: v ═ 2:1), reacted at 0-5 ℃, hydrochloric acid (1mol/L) was added dropwise to adjust the system pH to 2.0, and the system pH was constantly monitored to stabilize at 2.0 with stirring. 60ml of water was added to the reaction solution, and the acetone was removed by rotary evaporation under reduced pressure, excess NaCl was added to the remaining solution, and 100ml of ethyl acetate-acetone (v: v ═ 2:1) was added to extract the compound, and the aqueous layer was separated and extracted once more with ethyl acetate-acetone (2: 1). The organic layer was collected, dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to remove the solvent, to give 16.63g of amoxicillin-sulbactam hybrid molecule as a pale yellow solid with a yield of 90.8% and a purity of 94.5%.1H NMR(600MHz,Chloroform-d)δ9.85(s,1H),9.29(d,J＝3.6Hz,1H,CONH),8.63(s,2H,),7.29(d,J＝6.3Hz,2H),6.80(d,J＝7.5Hz,2H),5.89-5.92(m,2H),5.58(s,1H),5.44(s,1H),5.20(d,J＝2.1Hz,1H),4.94(s,1H),4.56(s,1H),4.42(s,1H),3.67-3.71(dd,J＝3.4,2.1Hz,1H),3.28(s,1H),2.25(S,1H),1.52(s,3H),1.48(s,3H),1.36(d,J＝6.5Hz,6H)；13C NMR(151MHz,Chloroform-d)δ176.41(C＝O),172.18(C＝O),171.77(C＝O),169.81(C＝O),167.53(C＝O),146.32,129.94,128.76,127.74,118.90,83.43,80.56,75.71,67.82,65.38,63.29,55.15,53.02,51.13,37.83,28.36,24.76,19.88,18.79,18.64。
Example 3
Preparation of intermediate 1
Tetrabutylammonium hydrogen sulfate (26.4g, 0.078mol) was dissolved in 100ml of water and stirred at room temperature. After the pH was adjusted to 7(2N NaOH) (20ml), sulbactam sodium (10g, 0.039mol) was added, and the pH of the reaction system was adjusted back to 6.9 with 2N NaOH, 150ml of methylene chloride was added, and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was washed with 150ml of dichloromethane, the organic layers were combined, dried over anhydrous MgSO4 and spin dried to give an oil. Vacuum drying to obtain 23.58g of intermediate 1, with 93.3% yield and 85.2% purity.
Preparation of intermediate 2
The resulting intermediate 1(23.58g, 0.36mol) was dissolved in 460mL of chlorobromomethane containing 3mL of pyridine (0.039mol), stirred at room temperature for 3.5h in the absence of light, and the reaction mixture was washed with a separatory funnel in the following order: 300ml of water, 300ml of saturated sodium sulfate solution, 300ml of saturated NaCl solution, the organic phase was collected and concentrated under reduced pressure to give 10.88g of intermediate 2 as a pale yellow solid with a yield of 92.6% and a purity of 86.3%.1HNMR(600MHz,Chloroform-d)δ5.64-5.94(dd,J＝8.8,11.2Hz,2H,CH2),4.64-4.66(m,1H),4.42(s,1H,),3.42-3.53(dd,J＝7.1,6.3Hz,2H),1.63(s,3H),1.46(s,3H)；13C NMR(151MHz,Chloroform-d)δ170.72(C＝O),165.47(C＝O),69.39,62.77,62.74,60.96,38.31,21.10,18.33。
Preparation of intermediate 3
The obtained intermediate 2(10.88g, 0.033mol) was dissolved in 100mL of acetone, NaI (4.95g, 0.033mol) was added thereto, and the mixture was stirred at room temperature for 16 hours, after completion of the reaction, the temperature of the system was lowered to 0 to 5 ℃ and the pH of the system was adjusted to neutral with a saturated sodium bicarbonate solution, followed by addition of 1mol/L sodium thiosulfate for decolorization. And finally, adding 100mL of water, keeping the temperature of 0-5 ℃, continuing stirring for 30min, separating out a large amount of white crystals, filtering and collecting a filter cake, washing the filter cake with water, and performing vacuum drying for 6h to obtain 11.34g of white solid, wherein the yield is 90.4%, and the purity is 98.2%.
Preparation of intermediate 4
Suspending anhydrous potassium carbonate (7.6g, 0.055mol) in DMF (150mL), adding amoxicillin trihydrate 25.2g (0.06mol), adding methyl acetoacetate 6.48mL (0.06mol), stirring at room temperature for 2h, cooling the solution to 0-5 ℃, continuing stirring for 4h, filtering the solution, and collecting the filtrate. Adding 250ml of diethyl ether into the filtrate, continuously stirring for 5min at 0-5 ℃, standing for 30min, pouring out the upper layer liquid, adding 100ml of diethyl ether for 2 times until no new precipitate is generated, filtering to remove diethyl ether, washing the filter residue with diethyl ether once, and then drying in vacuum to obtain 423.92g of an intermediate, which is light yellow solid, the yield is 72.5%, and the purity is 84.3%.1HNMR(600MHz,Chloroform-d)δ10.71(s,1H,COOH),9.24(d,J＝6.0Hz,1H,CONH),8.85(d,J＝3.5Hz,1H,),7.14(d,J＝5.1Hz,2H),6.76(d,J＝8.5Hz,2H),5.47(d,J＝8.2Hz,1H),5.38-5.40(m,J＝8.1Hz,1H),5.27(d,J＝4.2Hz,1H),4.45(s,1H),3.88(s,1H),3.52(s,3H),3.41(s,3H),1.76(s,3H),1.56(s,3H),1.42(s,3H)；13C NMR(151MHz,Chloroform-d)δ173.45(C＝O),170.68(C＝O),169.94(C＝O),169.85(C＝O),160.66,158.30,128.93,127.82,127.78,115.99,83.45,74.61,66.92,64.88,58.17,57.50,50.03,31.63,27.96,19.67。
Preparation of intermediate 5
Dissolving intermediate 4(13.82g, 0.030mol) in 250ml of DMF, stirring at 5-10 ℃, adding intermediate 3(11.34g, 0.030mol) in multiple times, keeping the temperature low, continuously stirring for 3.5h, pouring the reaction solution into a cold mixed solution of 200ml of ethyl acetate and 100ml of saturated calcium chloride after the reaction is finished, and separating an organic layer (extraction). The organic layer was washed with 50ml of saturated calcium chloride and filtered through celite. The filtrate was rotary dried under reduced pressure to give 19.41g of intermediate 5 as a pale yellow solid in 84.2% yield and 91.7% purity.1HNMR(600MHz,Chloroform-d)δ9.75(s,1H),9.26(d,J＝5.6Hz,1H,CONH),8.58(s,2H,),7.27(d,J＝7.1Hz,2H),6.83(d,J＝4.6Hz,2H),5.84-5.88(m,2H),5.51(s,1H),5.25(d,J＝2.1Hz,1H),4.90(s,1H),4.76(s,1H),4.48(s,1H),3.64-3.69(dd,J＝2.4,4.1Hz,1H),3.45(s,3H),3.22(s,1H),1.76(s,3H),1.54(s,3H),1.46(s,3H),1.33(d,J＝7.2Hz,6H)。
Preparation of amoxicillin-sulbactam hybrid molecule
Intermediate 5(20.3g, 0.025mol) was dissolved in 150mL of acetone water (v: v ═ 2:1), reacted at 0-5 ℃, p-methoxybenzenesulfonic acid (1mol/L) was added dropwise to adjust the pH of the system to 2.0, stirred and the pH of the system was continuously monitored to stabilize at 2.0. 60ml of water was added to the reaction solution, and the acetone was removed by rotary evaporation under reduced pressure, excess NaCl was added to the remaining solution, and 100ml of ethyl acetate-acetone (v: v ═ 2:1) was added to extract the compound, and the aqueous layer was separated and extracted once more with ethyl acetate-acetone (2: 1). The organic layer was collected, dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure to remove the solvent, to give 14.85g of amoxicillin-sulbactam hybrid molecule as a pale yellow solid with a yield of 93.4% and a purity of 96.5%.1H NMR(600MHz,Chloroform-d)δ9.85(s,1H),9.29(d,J＝3.6Hz,1H,CONH),8.63(s,2H,),7.29(d,J＝6.3Hz,2H),6.80(d,J＝7.5Hz,2H),5.89-5.92(m,2H),5.58(s,1H),5.44(s,1H),5.20(d,J＝2.1Hz,1H),4.94(s,1H),4.56(s,1H),4.42(s,1H),3.67-3.71(dd,J＝3.4,2.1Hz,1H),3.28(s,1H),2.25(S,1H),1.52(s,3H),1.48(s,3H),1.36(d,J＝6.5Hz,6H)；13C NMR(151MHz,Chloroform-d)δ176.41(C＝O),172.18(C＝O),171.77(C＝O),169.81(C＝O),167.53(C＝O),146.32,129.94,128.76,127.74,118.90,83.43,80.56,75.71,67.82,65.38,63.29,55.15,53.02,51.13,37.83,28.36,24.76,19.88,18.79,18.64。
Example 4: in-vitro antibacterial activity research of amoxicillin-sulbactam hybrid molecule
1. The test method comprises the following steps: the Minimum Inhibitory Concentration (MIC) of the test strain was determined by broth double dilution. The inoculum size of the bacteria was 105CFU/ml, and each drug was replicated 3 times for each bacteria. After the tested substance is dissolved with dimethyl sulfoxide, sterilized distilled water or lower alcohol is used to prepare solution.
2. Test strains: the total number of 8 laboratory standard strains (including 4 strainsGram-positive bacteria (G)+) 4 gram-negative bacteria (G)-)). Staphylococcus aureus ATCC29213(Staphylococcus aureus), Staphylococcus aureus ATCC11632(Staphylococcus aureus), Methicillin-Resistant Staphylococcus aureus (Methiocillin Resistant Staphylococcus aureus, MRSA), Streptococcus pneumoniae ATCC49619(Streptococcus pneumaniae), Escherichia coli ATCC25922(Escherichia coli), Salmonella LS677(Salmonella Enteritidis), Salmonella GD836(Salmonella Enteritidis), Salmonella GD828(Salmonella Enteritidis), Salmonella GD3625(Salmonella Enteritidis);
3. the positive control drug is amoxicillin.
The MIC values for the amoxicillin-sulbactam hybrid molecule and the control drug amoxicillin are listed in table 1.
TABLE 1 in part of the in vitro antibacterial Activity data (MIC, μ g/ml) for the target Compounds
As shown in the table 1, the amoxicillin-sulbactam hybrid molecule prepared by the invention has obvious antibacterial activity. For the measured G+、G-Bacteria: the antibacterial activity of the hybrid molecule to staphylococcus aureus, MRSA, escherichia coli and salmonella is superior to that of amoxicillin serving as a contrast medicament, and especially the antibacterial activity to methicillin-resistant staphylococcus aureus (MRSA) is remarkably superior to that of amoxicillin serving as a contrast medicament.
Application example 1: antibacterial active powder
1 part of the compound (amoxicillin-sulbactam hybrid molecule) in example 1, 1 part of polyvinylpyrrolidone and 8 parts of starch are prepared into powder according to the conventional method in the field.
Compared with the prior art, the invention connects two different lead compounds together through covalent bonds, and generates synergistic action, additive action or new pharmacological activity in vivo; the amoxicillin-sulbactam hybrid molecule prepared by the invention can be completely degraded into amoxicillin and sulbactam in vivo, generates a synergistic effect, enhances the antibacterial activity, and is effective to drug-resistant bacteria.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. A method for synthesizing an amoxicillin-sulbactam hybrid molecule is characterized in that: the method comprises the following steps:
s1, taking sulbactam acid as a raw material, and reacting the sulbactam acid with tetrabutylammonium hydrogen sulfate in water to form salt to obtain an intermediate 1;
s2, carrying out substitution reaction on the intermediate 1 prepared in the step S1 and bromochloromethane in the presence of pyridine to prepare an intermediate 2;
s3, iodinating the intermediate 2 prepared in the step S2 in an organic solvent through NaI to obtain an intermediate 3;
s4, taking amoxicillin trihydrate as a raw material, and carrying out dehydration condensation on the amoxicillin trihydrate and methyl acetoacetate in an organic solution to obtain an intermediate 4;
s5, carrying out substitution reaction on the intermediate 3 prepared in the step S3 and the intermediate 4 prepared in the step S4 in the presence of potassium carbonate to obtain an intermediate 5;
s6, placing the intermediate 5 prepared in the step S5 in an acetone aqueous solution, and removing side chains on amino groups through strong acid to obtain the amoxicillin-sulbactam hybrid molecule.
2. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the molar equivalent of tetrabutylammonium hydrogen sulfate in the step S1 is 2.0-2.5.
3. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the S2 specifically includes the following steps:
s21, dissolving the intermediate 1 prepared in the step S1 in bromochloromethane containing pyridine, and stirring at room temperature in a dark place for 3.5-4.5 h;
s22, the reaction mixture of step S21 is washed with water, a saturated sodium sulfate solution and saturated brine in this order, and the organic layer is collected and dried over anhydrous magnesium sulfate to obtain intermediate 2.
4. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 3, characterized in that: in the step S21, the molar equivalent of pyridine is 0.5-1.5, and the molar equivalent of chlorobromomethane is 200-300.
5. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the step S3 specifically includes the following steps:
s31, dissolving the intermediate 2 obtained in the step S2 in an organic solvent, adding NaI with the molar equivalent of 1.5-5 for iodination, and stirring at room temperature in a dark place for 5-16 hours; the organic solvent is one or a mixture of more than two of dichloromethane, acetone and ethyl acetate;
s32, after the reaction is finished, reducing the temperature of the solution to 0-5 ℃, keeping stirring, adjusting the pH to 3.0-7.3 by using saturated sodium bicarbonate, and then dropwise adding 1-5 mol/L sodium thiosulfate solution to decolorize the solution;
and S33, adding water with the same volume as the organic solvent, continuously stirring until white crystals are separated out, filtering and collecting filter residues, and performing vacuum drying at 25-50 ℃ to obtain an intermediate 3.
6. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the step S4 specifically includes the following steps:
s41, suspending alkali in an organic solvent, adding methyl acetoacetate and amoxicillin trihydrate, and stirring at room temperature for 1-6 h; the organic solvent is one of N, N-dimethylformamide, chloroform and N, N-dimethyl sulfoxide, and the alkali is one of potassium carbonate, sodium carbonate and sodium bicarbonate;
s42, filtering to remove the solvent, washing filter residues twice with diethyl ether, and performing vacuum drying at 30-50 ℃ to obtain an intermediate 4.
7. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the step S5 specifically includes the following steps:
s51, dissolving the intermediate 4 obtained in the step S4 in an organic solvent, reducing the temperature of the solution to 5-10 ℃, adding the intermediate 3 obtained in the step S3 in batches, and stirring for 2-8 hours; the organic solvent is one of N, N-dimethylformamide, chloroform and N, N-dimethyl sulfoxide;
s52, after the reaction is finished, pouring the solution into a mixed solution of ethyl acetate and saturated calcium chloride, extracting and layering, collecting an organic layer, washing the organic layer with a saturated calcium chloride solution at 25 ℃, adding diatomite for filtering, concentrating the filtrate under reduced pressure, and drying in vacuum to obtain an intermediate 5; the mixing volume ratio of the mixed solution is ethyl acetate: the saturated calcium chloride solution is 1: 1-3: 1.
8. A process for the synthesis of an amoxicillin-sulbactam hybrid molecule according to claim 1, characterized in that: the step S6 specifically includes the following steps:
s61, dissolving the intermediate 5 obtained in the step S5 in a mixed solution, reducing the temperature of the solution to 0-5 ℃, adding strong acid, stirring and continuously monitoring the pH value of the system to be stable at 1.0-4.0; the mixing volume ratio of the mixed solution is acetone: 1: 2-3: 1;
s62, evaporating the organic solvent under reduced pressure, adding excessive NaCl into the residual solution, adding an ethyl acetate-acetone mixed solution for extraction and layering, collecting an organic layer, removing water through anhydrous sodium sulfate, and then performing reduced pressure spin drying to obtain an amoxicillin-sulbactam heterozygous molecule; the mixing volume ratio of the mixed solution is ethyl acetate: acetone ═ 1: 1-4: 1.
9. An antibacterially active composition comprising an amoxicillin-sulbactam hybrid molecule, characterized in that: the content of the amoxicillin-sulbactam heterozygote is 0.1 wt% -99.5 wt%, and the balance is pharmaceutic adjuvant.
10. An antibacterially active composition comprising an amoxycillin-sulbactam hybrid molecule as claimed in claim 9, wherein: the pharmaceutic adjuvant is one or a mixture of more than two of polyvinylpyrrolidone K30, poloxamer 188, tween 80, span or starch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584840.9A CN112724162B (en) | 2020-12-28 | 2020-12-28 | Synthesis method and application of amoxicillin-sulbactam hybrid molecule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584840.9A CN112724162B (en) | 2020-12-28 | 2020-12-28 | Synthesis method and application of amoxicillin-sulbactam hybrid molecule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112724162A true CN112724162A (en) | 2021-04-30 |
| CN112724162B CN112724162B (en) | 2022-06-10 |
Family
ID=75606827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011584840.9A Active CN112724162B (en) | 2020-12-28 | 2020-12-28 | Synthesis method and application of amoxicillin-sulbactam hybrid molecule |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112724162B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0061274A1 (en) * | 1981-03-23 | 1982-09-29 | Pfizer Inc. | Process and intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanates |
| EP0074777A1 (en) * | 1981-09-09 | 1983-03-23 | Pfizer Inc. | Antibacterial 6-(2-amino-2-(4-acyloxy-phenyl) acetamido) penicillanoyloxymethyl esters |
| US4381263A (en) * | 1981-03-23 | 1983-04-26 | Pfizer Inc. | Process for the preparation of penicillanic acid esters |
| EP0082666A1 (en) * | 1981-12-22 | 1983-06-29 | Pfizer Inc. | Bis-hydroxymethyl carbonate bridged antibacterial agents |
| GB2231049A (en) * | 1989-04-14 | 1990-11-07 | Yoshitomi Pharmaceutical | Method for producing diester compounds |
-
2020
- 2020-12-28 CN CN202011584840.9A patent/CN112724162B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0061274A1 (en) * | 1981-03-23 | 1982-09-29 | Pfizer Inc. | Process and intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanates |
| US4381263A (en) * | 1981-03-23 | 1983-04-26 | Pfizer Inc. | Process for the preparation of penicillanic acid esters |
| EP0074777A1 (en) * | 1981-09-09 | 1983-03-23 | Pfizer Inc. | Antibacterial 6-(2-amino-2-(4-acyloxy-phenyl) acetamido) penicillanoyloxymethyl esters |
| EP0082666A1 (en) * | 1981-12-22 | 1983-06-29 | Pfizer Inc. | Bis-hydroxymethyl carbonate bridged antibacterial agents |
| GB2231049A (en) * | 1989-04-14 | 1990-11-07 | Yoshitomi Pharmaceutical | Method for producing diester compounds |
Non-Patent Citations (2)
| Title |
|---|
| 奚绍祁 等: "青霉烷砜酸、VD1827及其类似物的合成", 《医药工业》 * |
| 姜乃才 等: "氨苄青霉烷砜酸β-萘磺酸盐及其类似物的合成", 《医药工业》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112724162B (en) | 2022-06-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0984020B1 (en) | Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof. | |
| CN102329272B (en) | Method for preparing quinocetone | |
| CN112358427A (en) | Synthetic method of trifluoro-methyl-thionate compound | |
| CN103755722B (en) | The synthetic method of a kind of Levofloxacin and Ofloxacine USP 23 | |
| CN103554203A (en) | Amorphous crystal of tylonolide, and preparation method thereof | |
| CN112724162B (en) | Synthesis method and application of amoxicillin-sulbactam hybrid molecule | |
| SU1055332A3 (en) | Process for preparing 2-cyano-6-hydroxybenzthiazole | |
| CN103992337B (en) | A kind of method preparing Aspoxicillin sodium easily | |
| CN101337970A (en) | Method for synthesizing antibiotic cefpirome sulfate | |
| CN109134331B (en) | Synthesis method of azithromycin genotoxic impurity | |
| CN106279207A (en) | A kind of synthetic method of cefdinir | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| US8871927B2 (en) | Method for purifying Ceftizoxime sodium | |
| CN109912625B (en) | Process method for reducing ceftazidime impurity H | |
| CN1305876C (en) | One-step method for preparing high-purity cefpoxime proxetil | |
| CN102911186A (en) | Ceftizoxime sodium preparation and refining method | |
| LU501331B1 (en) | Synthesis method and application of amoxicillin-sulbactam hybrid molecule | |
| CN101550148B (en) | Refining method of Cefpodoxime proxetil compound | |
| EP0007689B1 (en) | Production of sodium cephamandole derivatives | |
| CN115093431B (en) | Method for synthesizing cefpodoxime proxetil | |
| CN102643293A (en) | Cefdinir ternary complex and method for preparing cefdinir by using same | |
| CN108299468B (en) | Refining method of cefprozil | |
| CN112521435B (en) | Application of roxithromycin analogue in preparation of antibacterial drugs | |
| CN111233894B (en) | Cefditoren pivoxil delta3Process for the preparation of isomers | |
| CN103030650A (en) | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |