CN111440194A - Amoxicillin derivative and preparation method and application thereof - Google Patents

Amoxicillin derivative and preparation method and application thereof Download PDF

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Publication number
CN111440194A
CN111440194A CN202010323859.1A CN202010323859A CN111440194A CN 111440194 A CN111440194 A CN 111440194A CN 202010323859 A CN202010323859 A CN 202010323859A CN 111440194 A CN111440194 A CN 111440194A
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compound
amoxicillin
pharmaceutically
derivative
amino
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方炳虎
林浩
陈良柱
李仲林
潘志坤
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Guangdong Wens Dahuanong Biotechnology Co ltd
South China Agricultural University
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Guangdong Wens Dahuanong Biotechnology Co ltd
South China Agricultural University
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    • 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
    • C07D499/21—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 a nitrogen atom 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
    • 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
    • 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

Abstract

The invention provides an amoxicillin derivative with a structure shown in a formula I or a pharmaceutically and/or veterinarily acceptable solvate thereof; wherein: r is hydrogen atom, alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl or a group containing one of alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl. The invention connects two different lead compounds together through covalent bond, and generates synergistic effect, additive effect or new pharmacological activity in vivo; the benzoic acid is spliced on an amoxicillin side chain to generate a new amoxicillin-benzoic acid derivative, and the obtained new compound can broaden the antibacterial spectrum, has good antibacterial activity on gram-positive bacteria and gram-negative bacteria, and is effective in drug-resistant bacteria.

Description

Amoxicillin derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to an amoxicillin derivative and a preparation method and application thereof.
Background
With the increasing serious drug resistance problem of veterinary clinical bacteria, the dosage of common antibacterial drugs for bacterial infectious diseases is higher, and the public health problems such as veterinary drug residues and drug resistance are highlighted, particularly, the broad spectrum β -lactamase escherichia coli (ESB L s-producing e.coli), vancomycin-resistant pseudomonas aeruginosa (VRP) and enterococcus (VRE), methicillin-resistant staphylococcus aureus (MRSA), penicillin-resistant streptococcus pneumoniae (PRSP) and the like bring more serious threats to the health of human beings and animals at present.
In the past, antibacterial drugs are developed by focusing on compounds with a single target spot, and even if new drugs with brand-new chemical structures aiming at new targets of bacteria appear, the bacteria can quickly generate a drug resistance mechanism aiming at the new targets to resist the drugs. Aiming at the characteristics of drug-resistant bacteria, many scientists now move the attention to the design and development of a composition, namely, on the basis of the original development of a single-target compound, the research and development of a multi-target compound and an antibacterial drug with dual functions are started. The Combination principle (Combination principles) is mainly to combine the structures of two drugs in one molecule, or to make the pharmacophores of the two drugs compatible in one molecule, called hybrid molecules (hybrids), and the newly formed hybrid molecules have the properties of both, so as to enhance the pharmacological action, reduce the respective toxic and side effects, or make the two get strong and short, exert the respective pharmacological activities, and cooperatively complete the treatment process. Nowadays, split drugs have become a new focus of current international drug development.
β -lactam antibiotics all have β -lactam rings, including penicillins, cephalosporins, thiomycins, monocycle β -lactams, carbapenems and the like, which have similar action mechanisms and can inhibit the synthesis of cell wall mucin synthase, namely, Penicillin Binding Proteins (PBPs), thereby inhibiting the synthesis of cell wall mucin, causing the cell wall of bacteria to be defective, causing the bacteria to swell and crack, and simultaneously generating antibacterial action by means of the autolytic enzyme dissolution of the bacteria.
The general antibacterial synergist is a kind of all substances which can enhance the antibacterial activity of antibacterial drugs when being used with the antibacterial drugs, the renal excretion inhibitor, β -lactamase inhibitor and β -lactam antibiotics are used with the antibacterial drugs, the antibacterial action of the latter can be enhanced by mechanisms of improving blood concentration or enzyme inhibition, reducing bacterial drug resistance and improving treatment effect, the company Pfizer develops a novel antibacterial drug sultamicin (sultamicilin) by ester bond connection of penicillin antibiotics ampicillin and sultam (β -lactamase inhibitor) by utilizing the principle of drug combination, the oral effect is good, the sultamicilin and ampicillin are decomposed when reaching the action part, the double action of the antibacterial drugs and inhibiting β -lactamase is achieved, the antibacterial spectrum of the ampicillin is expanded, and the antibiotic is sensitive to various gram positive and negative bacteria.
The combination in medicinal chemistry is one of the important methods for optimizing lead compounds, and aims to connect two same or different lead compounds or medicaments together through covalent bonds to generate a synergistic effect, an additive effect or new pharmacological activity in vivo. Therefore, the benzoic acid and the derivatives thereof are spliced on the side chain of amoxicillin to generate new amoxicillin-benzoic acid derivatives, and the obtained new compounds are expected to broaden the antibacterial spectrum and have the effect on drug-resistant bacteria.
Disclosure of Invention
The invention aims to provide a preparation method of an amoxicillin derivative and application thereof, and a high-efficiency and long-acting antibacterial active compound is obtained.
In the present invention, the term "pharmaceutically and/or veterinarily acceptable solvate" refers to a hydrate or a solvate soluble in C1-C4 alcohol or other organic vehicle.
The technical scheme of the invention is realized as follows:
the invention provides an amoxicillin derivative with a structure shown in a formula I or a pharmaceutically and/or veterinarily acceptable solvate thereof;
Figure BDA0002462458700000031
wherein: r is hydrogen atom, alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl or a group containing one of alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl.
As a further improvement of the invention, the compound has one of the following structures:
Figure BDA0002462458700000041
is named as (2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0]Heptane-2-formate-4-methoxy-benzoic acid methyl ester;
Figure BDA0002462458700000042
is named as (2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0]Heptane-2-formate-4-propoxy-benzoic acid methyl ester;
Figure BDA0002462458700000043
is named as (2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0]Heptane-2-formate-benzoic acid methyl ester;
Figure BDA0002462458700000044
is named as (2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0]Heptane-2-formate-4-nitro-benzoic acid methyl ester;
Figure BDA0002462458700000051
is named as (2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0]Heptane-2-carboxylate-4-dipropylsulfamoyl-benzoic acid methyl ester.
The invention further provides a preparation method of the amoxicillin derivative or the pharmaceutically and/or veterinarily acceptable solvate thereof, which comprises the following synthetic route:
Figure BDA0002462458700000052
as a further improvement of the invention, the method specifically comprises the following steps:
the method comprises the following steps: amino protection of amoxicillin
Adding the compound 1 (amoxicillin) and potassium carbonate into a DMF solution, dropwise adding an amino protective agent, continuing stirring after adding, and identifying the reaction end point by using a thin layer chromatography to obtain a compound 2;
step two: synthesis of chloromethyl ester Compound 4
Adding dimethyl formamide into the compound 3 to dissolve, adding an alkylating agent, adding a catalyst, and reacting at room temperature in a dark place to generate a chloromethyl ester compound 4;
step three: synthesis of composite 5
Adding dimethyl formamide into the compound 2 and the compound 4 at low temperature to react to generate a compound 5;
step four: synthesis of end product 6
Dissolving the compound 5 in methanol, dropwise adding a hydrochloric acid aqueous solution, and removing a protecting group to obtain a final product 6.
As a further improvement of the invention, the amino protective agent in the first step is one or a mixture of methyl acetoacetate, ethyl acetoacetate and benzaldehyde, preferably methyl acetoacetate, the alkylating agent in the second step is one or a mixture of chloroiodomethane and chlorobromomethane, preferably chloroiodomethane, the molar ratio of the compound 3 to the chloroiodomethane in the second step is 1 (5-10), the catalyst in the second step is one or a mixture of triethylamine, pyridine and sodium bicarbonate, preferably triethylamine, and the concentration of the hydrochloric acid aqueous solution in the fourth step is preferably 3 mol/L.
The invention further protects the application of the amoxicillin derivative or the pharmaceutically and/or veterinarily acceptable solvate thereof in preparing an antibacterial preparation.
The present invention further protects an antibacterially active composition comprising the above amoxicillin derivatives or pharmaceutically and/or veterinarily acceptable solvates thereof.
The present invention further protects an antibacterially active composition comprising an amoxicillin derivative as claimed in claim 1 or 2 or a pharmaceutically and/or veterinarily acceptable solvate thereof together with a pharmaceutically acceptable carrier or diluent.
As a further improvement of the invention, the dosage form of the antibacterial active composition is oral preparation or injection.
As a further improvement of the invention, the amoxicillin derivative or the pharmaceutically and/or veterinarily acceptable solvate thereof contains 0.1 wt% -99.5 wt% of the amoxicillin derivative or the pharmaceutically and/or veterinarily acceptable solvate, and the balance is a carrier or diluent.
The invention has the following beneficial effects: the invention connects two different lead compounds together through covalent bond, and generates synergistic effect, additive effect or new pharmacological activity in vivo; the benzoic acid is spliced on an amoxicillin side chain to generate a new amoxicillin-benzoic acid derivative, and the obtained new compound can broaden the antibacterial spectrum, has good antibacterial activity on gram-positive bacteria and gram-negative bacteria, and is effective in drug-resistant bacteria.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a drawing of Compound 6a1HNMR spectrogram;
FIG. 2 is a drawing of Compound 6b1HNMR spectrogram;
FIG. 3 is a drawing of Compound 6c1HNMR spectrogram;
FIG. 4 is a drawing of Compound 6d1HNMR spectrogram;
FIG. 5 is a drawing of Compound 6e1HNMR spectrogram.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The present invention provides a method for synthesizing amoxicillin-benzoic acid derivative split compounds, which is further illustrated by the following examples, which are not intended to limit the present invention in any way. In all examples, the melting points of the compounds were determined by capillary melting point apparatus, 1HNMR by a Varian AM-400 NMR spectrometer with TMS as internal standard and chemical shifts in (ppm); the mass spectrum was determined with a Q-TOF type mass spectrometer and the elemental analysis was determined with a CarloErball model 06 automatic elemental analyzer.
Silica gel used for column chromatography is produced by Qingdao ocean chemical plant (column chromatography H type), and a thin layer chromatography plate is purchased from GF254 type in the market.
The first embodiment is as follows: synthesis of Compound (2)
Suspending 7.6g of potassium carbonate in 10ml of dimethylformamide, cooling to 0 ℃, adding 10.8ml of methyl acetoacetate and 20.9g of amoxicillin trihydrate under the protection of nitrogen, continuing stirring for 6 hours in ice bath, adding equivalent diethyl ether into the reaction solution, stirring for 30min, standing for settling, adding equivalent diethyl ether into the lower layer, repeating the operation for 3 times, adding 2 times of acetone into the obtained lower-layer sticky matter to separate out a precipitate, filtering, washing with acetone, and drying in vacuum to obtain 20.5g of white or off-white solid, namely the compound (2).
IR(KBr,cm-1):3302.13(OH),2964.59,1772.58(C＝O),1664.57,1597.06,1508.33,1446.61,1392.61,1269.16,1172.72,1134.14；1H NMR(600MHz,DMSO-d6)10.70(s,1H,COOH),9.25(d,J＝8.3Hz,1H,CONH),8.86(d,J＝8.5Hz,1H,NH),7.13(d,J＝8.1Hz,2H),6.75(d,J＝8.2Hz,2H),5.48–5.44(m,1H),5.42–5.37(m,1H),5.30–5.26(m,1H),4.45(s,1H),3.88(s,1H),3.52(s,3H),1.76(s,3H),1.56(s,3H),1.42(s,3H)；HR-MS(ESI)Calcdfor C21H25N3O7S(M+H+):464.5050；Found:464.5057.
Example two: synthesis of Compounds (4a to e)
Adding 7.3g of benzoic acid into 50ml of N, N-dimethylformamide, sequentially adding 28ml of chloroiodomethane and 8ml of triethylamine, stirring for 5 hours at room temperature in a dark place, adding 100ml of water for dilution, extracting for 3 times by using 50ml of ethyl acetate, collecting an organic layer, washing by using saturated saline, drying by using anhydrous sodium sulfate, removing the solvent under reduced pressure, and drying in vacuum to obtain 7.4g of white solid, namely chloromethyl-benzoic acid ester (4 a). IR (KBr, cm)-1):2987.74,1741.72(C＝O),1597.06,1444.68,1342.46,1255.66,1174.65,1078.21；1HNMR(600MHz,Chloroform-d)8.10–8.06(d,2H),7.61(t,J＝7.4,1.4Hz,1H),7.46(t,J＝7.8Hz,2H),5.96(s,2H，CH2Cl)；HR-MS(ESI)Calcd for C8H7ClO2(M+H+):171.5273；Found:171.5276.
Chloromethyl-4-methoxybenzoate (4b) as a white solid; the yield is 45.42%; IR (KBr, cm)-1):2970.38,2845.00,1734.01(C＝O),1606.70,1510.26,1448.54,1334.74,1259.52,1172.72,1082.07,1024.20；1H NMR(600MHz,Chloroform-d)8.04–8.00(d,2H),6.92–6.90(d,2H),5.93(s,2H,CH2Cl),3.83(s,3H)；HR-MS(ESI)Calcd for C9H9ClO3(M+H+):201.5408；Found:200.5411.
Chloromethyl-4-propoxybenzoate (4c) as a white solid; the yield is 46.63 percent; IR (KBr, cm)-1):2968.45,2877.79,1735.93(C＝O),1606.70,1510.26,1438.90,1332.81,1257.59,1168.86,1080.14,1010.70；1H NMR(600MHz,Chloroform-d)8.03(d,2H),1H NMR(600MHz,Chloroform-d)8.03(d,J＝8.2Hz,2H),6.94(d,J＝8.2Hz,2H),5.95(s,2H,CH2Cl),3.99(s,2H),1.85(q,J＝7.1Hz,2H),1.06(t,J＝7.4Hz,3H)；HR-MS(ESI)Calcd for C11H13ClO3(M+H+):229.6723；Found:229.6726
Chloromethyl-4-nitrobenzoate (4d) as a white solid; the yield is 36.74 percent; IR (KBr, cm)-1):3005.10(benzene ring),1737.86,1604.77,1525.69,1433.11,1338.60,1253.73,1082.07,1010.70；1H NMR(600MHz,Chloroform-d)8.35–8.27(dd,4H),6.00(s,2H,CH2Cl)；HR-MS(ESI)Calcd for C8H6ClNO4(M+H+):216.5890；Found:216.5887.
Chloromethyl-4- (N, N-dipropylsulfonamido) benzoate (4e) as a white solid; the yield is 32.54%; IR (KBr, cm)-1):2972.31,2935.66,2873.94,1747.51(C＝O),1597.06,1450.47,1394.53,1342.46,1251.80,1157.29,1078.21；1H NMR(600MHz,Chloroform-d)1H NMR(600MHz,Chloroform-d)8.19(d,J＝8.6Hz,2H),7.90(d,J＝8.6Hz,2H),5.97(s,2H,CH2Cl),3.13–3.07(m,4H),1.58–1.51(m,4H),0.86(t,J＝7.4Hz,6H).(t,J＝7.4Hz,6H)；HR-MS(ESI)Calcdfor C14H20ClNO4S(M+H+):334.8270；Found:334.8276.
Example three: synthesis of Compounds (5a to e)
Dissolving 8.5g of the compound (4) in 30ml of anhydrous acetone, adding 15g of sodium iodide under the protection of nitrogen, stirring at room temperature for 2h, adding the reaction solution in an ice bath, dropwise adding 1 mol/L mol of sodium thiosulfate until the solution is decolorized, dropwise adding an equal amount of water to precipitate crystals, standing for 30min, filtering, washing with acetone, and directly using for the next reaction.
Dissolving 6.5g of the compound (2) in 50ml of N, N-dimethylformamide, cooling in an ice bath for 5-10 ℃, adding the reaction product in the previous step under the protection of nitrogen, continuously stirring for 3h, adding 100ml of water/ethyl acetate (1:1, v: v) mixed solution into the reaction solution, uniformly mixing, standing, separating, washing an organic layer with a saturated calcium chloride solution, concentrating under reduced pressure to remove the solvent to obtain a crude product, and purifying by a column to obtain the compound (5).
(2S,5R,6R) -6- [2- (2-methoxycarbonyl-1-methyl-vinyl) amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-formate-benzoic acid methyl ester (5a), light yellow solid; the yield is 72.68%; IR (KBr, cm)–1):3356.14(OH),3064.89,2974.23,1778.37(C＝O),1666.50,1600.92,1508.33,1448.54,1269.16,1168.86；1H NMR(600MHz,Chloroform-d)9.07(d,J＝7.0Hz,1H,CONH),8.07(d,J＝7.7Hz,2H),7.63(t,J＝7.5Hz,1H),7.48(t,J＝7.7Hz,2H),7.17(d,J＝8.3Hz,2H),6.91(d,J＝9.0Hz,1H,NH),6.72(d,J＝8.4Hz,2H),6.07(dd,J＝39.7,5.7Hz,2H,OCH2O),5.64(dd,J＝8.9,4.1Hz,1H),5.57–5.54(m,1H),5.03(d,J＝6.9Hz,1H),4.67(s,1H),4.48(s,1H),3.67–3.64(m,3H),1.93(s,3H),1.56(s,3H),1.46(s,3H)；13C NMR(151MHz,Chloroform-d)172.89(C＝O),170.95(C＝O),170.70(C＝O),166.43(C＝O),164.90(C＝O),160.11,156.70,134.00,130.04,128.64,128.36,116.37,85.94,80.03(OCH2O),70.11,68.01,61.20,60.41,58.81,50.47,26.72,21.03,19.78；HR-MS(ESI)Calcd for C29H31N3O9S(M+H+):598.6390；Found:598.6393.
(2S,5R,6R) -6- [2- (2-methoxycarbonyl-1-methyl-vinyl) amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azaBicyclo [3.2.0]Heptane-2-formate-4-methoxybenzoic acid methyl ester (5b), light yellow solid; the yield is 68.96%; IR (KBr, cm)-1):3363.86(OH),2972.31,2368.59,1782.23(C＝O),1604.77,1512.19,1446.61,1265.30,1170.79,1091.71,1022.27；1H NMR(600MHz,Chloroform-d)9.09(d,J＝7.0Hz,1H,CONH),8.02(d,J＝8.5Hz,2H),7.19(d,J＝8.1Hz,2H),6.95(d,J＝8.7Hz,2H),6.87(d,J＝9.2Hz,1H,NH),6.74(d,J＝8.1Hz,2H),6.09–6.00(m,2H,OCH2O),5.64(dd,J＝9.1,4.2Hz,1H),5.55(d,J＝4.0Hz,1H),5.03(d,J＝6.9Hz,1H),4.67(s,1H),4.48(d,J＝1.3Hz,1H),3.89(d,J＝1.3Hz,3H),3.65(s,3H),1.94(s,3H),1.55(s,3H),1.46(s,3H)；13C NMR(151MHz,Chloroform-d)172.84(C＝O),170.92(C＝O),170.62(C＝O),166.48(C＝O),164.54(C＝O),164.24,160.05,156.61,132.23,128.39,128.19,120.64,116.35,113.95,85.98,79.87(OCH2O),70.12,68.01,64.87,61.21,55.52,50.45,31.58,26.71,19.78；HR-MS(ESI)Calcd for C30H33N3O10S(M+H+):628.6650；Found:628.6646.
(2S,5R,6R) -6- [2- (2-methoxycarbonyl-1-methyl-vinyl) amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-formate-4-propoxybenzoic acid methyl ester (5c), light yellow solid; the yield is 73.56%; IR (KBr, cm)-1):3356.14(OH),2968.45,1780.30(C＝O),1600.92,1512.19,1444.68,1265.30,1166.93,1085.92；1H NMR(600MHz,Chloroform-d)9.08(d,J＝6.9Hz,1H,CONH),8.00(d,J＝7.6Hz,2H),7.18(d,J＝8.0Hz,2H),6.93(d,J＝8.7Hz,2H),6.88(d,J＝9.0Hz,1H,NH),6.74(d,J＝7.5Hz,2H),6.04(dd,J＝39.5,5.6Hz,2H,OCH2O),5.64(dd,J＝8.8,4.0Hz,1H),5.55(d,J＝4.1Hz,1H),5.03(d,J＝7.0Hz,1H),4.67(s,1H),4.47(s,1H),4.00(t,J＝6.5Hz,2H),3.65(s,3H),1.94(s,3H),1.85(q,J＝7.0Hz,2H),1.55(s,3H),1.46(s,3H),1.06(t,J＝7.4Hz,3H)；13C NMR(151MHz,Chloroform-d)172.85(C＝O),170.94(C＝O),170.66(C＝O),166.49(C＝O),164.59(C＝O),163.87,160.08,156.66,132.21,128.38,128.13,120.32,116.35,114.39,85.95,79.85(OCH2O),70.12,69.81,68.00,64.88,61.21,60.41,58.80,50.46,31.57,26.71,22.41,19.78,10.42；HR-MS(ESI)Calcd for C32H37N3O10S(M+H+):656.7790；Found:656.7194.
(2S,5R,6R) -6- [2- (2-methoxycarbonyl-1-methyl-vinyl) amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylate-4-nitrobenzoic acid methyl ester (5d), light yellow solid; the yield is 71.24%; IR (KBr, cm)-1):3369.64(OH),2974.23,2374.37,1780.30(C＝O),1670.35,1600.92,1521.84,1444.68,1269.16,1166.93,1087.85；1H NMR(600MHz,Chloroform-d)9.07(d,J＝6.8Hz,1H,CONH),8.29(dd,J＝51.0,8.0Hz,5H),7.18(d,J＝7.6Hz,2H),6.91(d,J＝8.8Hz,1H,NH),6.73(d,J＝7.6Hz,2H),6.12–6.07(m,2H,OCH2O),5.65(dd,J＝8.8,4.1Hz,1H),5.55(d,J＝4.0Hz,1H),5.03(d,J＝7.0Hz,1H),4.68(s,1H),4.50(s,1H),3.65(s,3H),1.94(s,3H),1.57(s,3H),1.47(s,3H)；13C NMR(151MHz,Chloroform-d)172.85(C＝O),170.85(C＝O),170.72(C＝O),166.30(C＝O),163.12(C＝O),160.09,156.68,151.14,133.70,131.19,128.35,128.04,123.80,116.36,116.00,86.01,80.32(OCH2O),70.08,68.06,64.79,61.20,60.41,58.88,52.36,50.48,49.84,31.61,30.13,19.78；HR-MS(ESI)Calcd for C29H30N4O11S(M+H+):643.6360；Found:643.6357.
(2S,5R,6R) -6- [2- (2-methoxycarbonyl-1-methyl-vinyl) amino-2- (4-hydroxyphenyl) acetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylate-4- (N, N-dipropylsulfonamido) benzoic acid methyl ester (5e), light yellow solid; the yield is 76.76%; IR (KBr, cm)-1):3365.78(OH),2968.45,2374.37,1782.23(C＝O),1664.57,1602.85,1510.26,1450.47,1336.67,1269.16,1163.08,1087.85；1H NMR(600MHz,Chloroform-d)9.07(d,J＝7.0Hz,1H,CONH),8.18(d,J＝8.1Hz,2H),7.91(d,J＝8.2Hz,2H),7.17(d,J＝8.1Hz,2H),6.99(d,J＝8.8Hz,1H,NH),6.75–6.67(m,2H),6.07(dd,J＝24.9,5.7Hz,2H,OCH2O),5.63(dd,J＝8.8,4.1Hz,1H),5.55(d,J＝4.0Hz,1H),5.03(d,J＝7.0Hz,1H),4.66(s,1H),4.50(d,J＝13.6Hz,1H),3.64(s,3H),3.12(t,J＝7.7Hz,4H),1.93(s,3H),1.61–1.52(m,7H),1.46(s,3H),0.88(t,J＝7.3Hz,6H)；13C NMR(151MHz,DMSO-d6)172.82(C＝O),171.03(C＝O),170.83(C＝O),166.35(C＝O),163.65(C＝O),160.17,156.84,145.35,131.62,130.68,128.34,127.94,127.22,116.36,85.88,80.23(OCH2O),70.08,68.02,64.80,61.17,58.90,50.50,49.95,31.60,26.72,21.94,19.80,11.14；HR-MS(ESI)Calcd for C35H44N4O11S2(M+H+):761.8740；Found:761.8734.
Example four: synthesis of the end products (6 a-e)
Dissolving the compound (5) in methanol, cooling the mixture in an ice bath to below 10 ℃, dropwise adding 3 mol/L hydrochloric acid aqueous solution while stirring until the pH value is 2, continuing stirring for 1h, adding 2 times of saturated sodium chloride solution, one time of acetone and one time of ethyl acetate into the reaction solution, separating the reaction solution, washing an organic layer for 2 times by using the saturated sodium chloride solution, removing the solvent under reduced pressure to obtain a crude product, and purifying the crude product by passing through a column to obtain a final product (6).
(2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetylamino]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-formate-benzoic acid methyl ester (6a), light yellow solid; yield: 87.48 percent; IR (KBr, cm)-1):3409.5(NH2),3201.3(OH),2975.6,2613.1,1770.3(C＝O),1689.3,1606.4,1515.8,1459.8,1268.9,1089.6；1HNMR(600MHz,DMSO-d6)9.83(s,1H,OH),9.28(d,J＝7.5Hz,1H,CONH),8.69(s,2H,NH2),7.96(d,J＝7.7Hz,2H),7.71(t,J＝7.4Hz,1H),7.56(t,J＝7.6Hz,3H),7.28(d,J＝8.1Hz,2H),6.79(d,J＝8.2Hz,2H),6.03(dd,J＝47.9,6.0Hz,2H,OCH2O),5.58(dd,J＝7.0,3.9Hz,1H),5.45(d,J＝4.1Hz,1H),4.95(s,1H),4.42(s,1H),1.47(s,3H),1.31(s,3H)；13C NMR(151MHz,DMSO-d6)173.33(C＝O),168.51(C＝O),166.81(C＝O),164.78(C＝O),158.65,134.74,129.93,129.57 128.60,124.18,115.77,80.83(OCH2O),70.10,67.39,64.38,58.67,54.98,29.99,26.66；HR-MS(ESI)Calcd forC24H25N3O7S(M+H+):499.5380；Found:499.5367.
(2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetylamino]-3, 3-dimethyl-7-oxo-4-thia-1-azaBicyclo [3.2.0]Heptane-2-formate-4-methoxybenzoic acid methyl ester (6b), light yellow solid; yield: 86.34 percent; IR (KBr, cm)-1):3459.7(NH2),3214.8(OH),2973.7,2591.9,1772.3(C＝O),1722.1,1666.2,1606.4,1515.8,1457.9,1263.1,1168.7,1095.4；1H NMR(600MHz,DMSO-d6)9.77(s,1H,OH),9.27(d,J＝7.6Hz,1H,CONH),8.64(s,2H,NH2),7.92(d,J＝8.1Hz,2H),7.27(d,J＝8.0Hz,2H),7.08(d,J＝8.1Hz,2H),6.78(d,J＝7.8Hz,2H),6.00(dd,J＝51.1,6.0Hz,2H,OCH2O),5.59(dd,J＝7.8,4.1Hz,1H),5.45(d,J＝4.0Hz,1H),4.94(s,1H),4.41(s,1H),3.84(s,3H),1.47(s,3H),1.30(s,3H).；13C NMR(151MHz,DMSO-d6)173.35(C＝O),168.41(C＝O),166.83(C＝O),164.48(C＝O),164.36,158.65,132.20,129.64,124.05,120.63,115.80,114.86,80.60(OCH2O),70.12,67.33,64.39,58.60,56.12,55.02,29.87,26.66；HR-MS(ESI)Calcd for C25H27N3O8S(M+H+):530.5640；Found:530.5637.
(2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetylamino]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-formate-4-propoxybenzoic acid methyl ester (6c), light yellow solid; yield: 88.47 percent; IR (KBr, cm)-1):3398.1(NH2),3205.1(OH),2967.9,2599.6,1772.3(C＝O),1693.2,1604.5,1513.8,1467.6,1261.2,1168.7,1087.7；1HNMR(600MHz,DMSO-d6)9.78(s,1H,OH),9.25(d,J＝7.5Hz,1H,CONH),8.56(s,2H,NH2),7.90(d,J＝8.3Hz,2H),7.27(d,J＝8.1Hz,2H),7.06(d,J＝8.3Hz,2H),6.78(d,J＝8.0Hz,2H),5.99(dd,J＝50.3,6.1Hz,2H,OCH2O),5.59(d,J＝4.9Hz,1H),5.45(d,J＝3.9Hz,1H),4.92(s,1H),4.41(d,J＝1.5Hz,2H),4.02(t,J＝6.9Hz,2H),1.47(s,3H),1.30(s,3H),0.97(t,J＝7.4Hz,3H)；13C NMR(151MHz,DMSO-d6)173.39(C＝O),168.62(C＝O),166.84(C＝O),164.36(C＝O),163.83,158.60,132.20,129.58,124.37,120.44,115.76,115.24,80.58(OCH2O),70.02(d,J＝29.2Hz),67.37,64.38,60.20,58.61,55.09,29.92,26.66,22.31,10.73；HR-MS(ESI)Calcdfor C27H31N3O8S(M+H+):558.6180；Found:558.6174.
(2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetylamino]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylate-4-nitrobenzoic acid methyl ester (6d), light yellow solid; yield: 89.67 percent; IR (KBr, cm)-1):3428.8(NH2),3224.4(OH),2975.6,2611.1,1766.5(C＝O),1691.3,1610.3,1525.4,1353.8,1270.9,1089.6；1H NMR(600MHz,DMSO-d6)9.78(s,1H,OH),9.26(d,J＝7.6Hz,1H,CONH),8.59(s,2H,NH2),8.37(d,J＝8.1Hz,2H),8.20(d,J＝8.0Hz,2H),7.27(d,J＝7.9Hz,2H),6.78(d,J＝7.9Hz,2H),6.07(dd,J＝38.6,6.2Hz,2H,OCH2O),5.59(t,J＝5.6Hz,1H),5.46(d,J＝4.1Hz,1H),4.94(s,1H),4.45(s,1H),1.48(s,3H),1.31(s,3H)；13C NMR(151MHz,DMSO-d6)173.29(C＝O),168.52(C＝O),166.76(C＝O),163.45(C＝O),158.62,151.21,134.00,131.47,129.62,124.61,124.21,115.77,81.24(OCH2O),70.06,67.40,64.41,58.70,55.04,30.06,26.70；HR-MS(ESI)Calcd for C24H24N4O9S(M+H+):545.5350；Found:545.5356.
(2S,5R,6R) -6- [ 2-amino-2- (4-hydroxyphenyl) acetylamino]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]Heptane-2-carboxylate-4- (N, N-dipropylsulfonamido) benzoic acid methyl ester (6e), light yellow solid; yield: 87.25 percent; IR (KBr, cm)-1):3405.7(NH2),3209.1(OH),2967.9,299.6,1762.6(C＝O),1687.4,1606.4,1515.8,1463.7,1334.5,1270.9,1159；1H NMR(600MHz,DMSO-d6)9.79(s,H,OH)9.24(s,1H,CONH),8.30(s,2H,NH2),8.14(d,J＝8.1Hz,2H),7.97(d,J＝8.1Hz,2H),7.27(d,J＝8.2Hz,2H),6.78(d,J＝8.2Hz,2H,OCH2O),1H NMR 6.08(dd,J＝39.4,6.5Hz,2H,OCH2O),5.58(d,J＝4.0Hz,1H),5.46(d,J＝4.1Hz,1H),4.91(s,1H),4.45(s,1H),3.05(dd,J＝8.5,6.5Hz,4H),1.50-1.41(m,7H),1.32(s,2H),0.79(t,J＝7.3Hz,6H)；13C NMR(151MHz,DMSO-d6)173.41(C＝O),169.05(C＝O),166.80(C＝O),163.80(C＝O),158.50,144.85,131.99,130.98,129.47,127.86,124.98,115.71,81.13(OCH2O),70.05,67.47,64.40,58.70,55.25,50.00,30.14,26.68,21.99,11.39；HR-MS(ESI)CalcdforC30H38N4O9S2(M+H+):663.7730；Found:663.7737.
Example five: in vitro antibacterial Activity Studies of some of the target Compounds of the present invention
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: there were 8 laboratory standard strains (including 4 gram-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 L S677(Salmonella Enteritidis), Salmonella GD836(Salmonella Enteritidis), Salmonella GD828(Salmonella Enteritidis), Salmonella GD3625(Salmonella Enteritidis), and 3. the positive control drug is amoxicillin.
MIC values for the respective compounds are shown in Table 1
TABLE 1 in part of the in vitro antibacterial Activity data (MIC, μ g/ml) for the target Compounds
Figure BDA0002462458700000181
As can be seen from Table 1, the compounds of the present invention have significant antibacterial activity.
For the measured G+Bacteria: the antibacterial activity of 6d and 6e to staphylococcus aureus, MRSA and escherichia coli 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; the antibacterial activity to salmonella is 6d, 6e, to G measured-Bacteria: compounds 6d, 6e both showed moderate resistance to 4G-strains testedAnd (4) bacterial activity.
Application example 1 an antibacterial active premix
1 part of the compound (6d) of example four, 1 part of polyvinylpyrrolidone and 5 parts of starch are prepared into a premix 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 benzoic acid is spliced on an amoxicillin side chain to generate a new amoxicillin-benzoic acid derivative, and the obtained new compound can broaden the antibacterial spectrum, has good antibacterial activity on gram-positive bacteria and gram-negative bacteria, and is effective in drug-resistant bacteria.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. An amoxicillin derivative having the structure of formula i or a pharmaceutically and/or veterinarily acceptable solvate thereof;
Figure FDA0002462458690000011
wherein: r is hydrogen atom, alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl or a group containing one of alkyl, amino, hydroxyl, amidino, guanidino, nitro, sulfonyl.
2. The amoxicillin derivative or pharmaceutically and/or veterinarily acceptable solvate thereof according to claim 1, characterized by having one of the following structures:
Figure FDA0002462458690000012
Figure FDA0002462458690000021
3. a process for the preparation of an amoxicillin derivative as defined in claim 1 or 2 or a pharmaceutically and/or veterinarily acceptable solvate thereof, characterized by the following synthetic route:
Figure FDA0002462458690000022
4. the preparation method according to claim 3, characterized by comprising the following steps:
the method comprises the following steps: amino protection of amoxicillin
Adding the compound 1 (amoxicillin) and potassium carbonate into a DMF solution, dropwise adding an amino protective agent, continuing stirring after adding, and identifying the reaction end point by using a thin layer chromatography to obtain a compound 2;
step two: synthesis of chloromethyl ester Compound 4
Adding dimethyl formamide into the compound 3 to dissolve, adding an alkylating agent, adding a catalyst, and reacting at room temperature in a dark place to generate a chloromethyl ester compound 4;
step three: synthesis of composite 5
Adding dimethyl formamide into the compound 2 and the compound 4 at low temperature to react to generate a compound 5;
step four: synthesis of end product 6
Dissolving the compound 5 in methanol, dropwise adding a hydrochloric acid aqueous solution, and removing a protecting group to obtain a final product 6.
5. The preparation method according to claim 4, wherein the amino protective agent in the first step is one of methyl acetoacetate, ethyl acetoacetate and benzaldehyde, the alkylating agent in the second step is one of chloroiodomethane and chlorobromomethane, the molar ratio of the compound 3 to the chloroiodomethane in the second step is 1 (5-10), the catalyst in the second step is one or a mixture of triethylamine, pyridine and sodium bicarbonate, and the concentration of the hydrochloric acid aqueous solution in the fourth step is preferably 3 mol/L.
6. Use of an amoxycillin derivative as claimed in claim 1 or 2, or a pharmaceutically and/or veterinarily acceptable solvate thereof, for the manufacture of an antibacterial formulation.
7. An antibacterially active composition comprising an amoxycillin derivative as claimed in claim 1 or claim 2, or a pharmaceutically and/or veterinarily acceptable solvate thereof.
8. An antibacterially active composition comprising an amoxycillin derivative as claimed in claim 1 or claim 2, or a pharmaceutically and/or veterinarily acceptable solvate thereof, and a pharmaceutically acceptable carrier or diluent.
9. The antimicrobially active composition according to claim 7, wherein the antimicrobially active composition is in the form of an oral dosage form or an injectable dosage form.
10. The antibacterially active composition of claim 7 wherein the amoxicillin derivative or pharmaceutically and/or veterinarily acceptable solvate thereof is present in an amount of 0.1 wt% to 99.5 wt%, with the balance being a carrier or diluent.
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EP0061281A1 (en) * 1981-03-23 1982-09-29 Pfizer Inc. Bis-esters of methanediol with acetonides of ampicillin or amoxicillin and penicillanic acid 1,1-dioxide
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