CN103965214B - A kind of beta-lactam compound and its preparation method and application - Google Patents
A kind of beta-lactam compound and its preparation method and application Download PDFInfo
- Publication number
- CN103965214B CN103965214B CN201410232591.5A CN201410232591A CN103965214B CN 103965214 B CN103965214 B CN 103965214B CN 201410232591 A CN201410232591 A CN 201410232591A CN 103965214 B CN103965214 B CN 103965214B
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- beta
- solution
- lactam compound
- preparation
- medicine
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
-
- 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
- C07D499/10—Modification of an amino radical directly attached in position 6
- C07D499/12—Acylation
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Abstract
The invention discloses a kind of beta-lactam compound, its chemical structural formula is:
Description
Technical field
The present invention relates to a kind of beta-lactam compound, also relate to preparation method and the application of above-mentioned beta-lactam compound.
Background technology
Sulfa drugs is born in 1932, is the synthetic antimicrobial DP finish applied the earliest.Sulfa drugs stable in properties, use simple, low price, be convenient to long-term preservation.Sulfa drugs determined curative effect, can suppress most of gram-positive microorganism and some Gram-negative bacterias, it also has good restraining effect to some fungi.Wherein the most responsive is suis, streptococcus pneumoniae etc.In the anti-infective history of the mankind, be once widely used in the disease for the treatment of and being caused by above-mentioned cause pathogeny imcrobe infection, the development history of antibacterials occupied critical role.
β-lactam antibitics refers to the microbiotic containing beta-lactam ring in molecule, and be a maximum class microbiotic, clinical application is maximum.From nineteen forty-one, penicillin G has been widely used in clinical., there is first generation cephalosporin in successful application head spore rhzomorph I in 1962.From the sixties in 20th century, the semi-synthetic penicillins microbiotic of a series of wide spectrum, antiacid, resistance to enzyme is constantly brought to clinical.Meanwhile, cephalosporins is develop rapidly also, has the s-generation, the third generation and forth generation cynnematin to go on the market in a large number respectively to 20 century 70s, the eighties, the nineties.But along with the continuous appearance of drug-resistant bacteria, the germ resistance of existing microbiotic to new bacteria reduces gradually, therefore develop a kind of novel ss-lactam compounds with good anti-microbial activity necessary.
Summary of the invention
Goal of the invention: technical problem to be solved by this invention is to provide a kind of novel ss-lactam compounds with good anti-microbial activity, both there is in this compound the feature pharmacophoric group of sulfa drugs, there is again the feature pharmacophoric group of Beta-lactam medicine.
The technical problem that the present invention also will solve is to provide the preparation method of above-mentioned beta-lactam compound.
The technical problem that the present invention finally will solve is to provide the application of above-mentioned beta-lactam compound in anti Bacillus pyocyaneu Flugge activity.
Summary of the invention: for solving the problems of the technologies described above, the technical solution adopted in the present invention is:
A kind of beta-lactam compound, its chemical structural formula is:
The preparation method of above-mentioned beta-lactam compound, comprises the steps:
Step 1, by a certain amount of NaHCO
3or KHCO
3add in aqueous acetone solution;
Step 2,7-ADCA or 6-APA adding aequum in the solution of step 1 reacts, and adds the p-nitrobenzene sulfonyl chloride of aequum after reaction again in solution, fully filters after reaction, obtains filtrate;
Step 3, acetone in filtrate is steamed after removing, with the impurity in ethyl acetate washing soln removing solution, in solution, then instill the pH value of appropriate oxalic acid solution regulator solution again, by ethyl acetate, solution is extracted again, extraction liquid condensing crystal is obtained intermediate product;
Step 4, is dissolved in intermediate product in aprotic solvent, under Pd/C catalysis, passes into hydrogen and carries out hydrogenation reaction, filters, carry out condensing crystal, or add poor solvent to filtrate in filtrate after reaction, separates out solid, obtains required product.
Wherein, in step 4, described aprotic solvent is ethyl acetate, tetrahydrofuran (THF), dioxane.
Wherein, in step 4, described poor solvent is sherwood oil, heptane, hexane, hexanaphthene or ether.
The application of above-mentioned beta-lactam compound in anti Bacillus pyocyaneu Flugge activity.
Beneficial effect: the present invention obtains one by the synthesis of medicine principle of hybridization and both had sulfa drugs feature pharmacophoric group (to this sulphonamide amino), there is again the beta-lactam compound of Beta-lactam medicine feature pharmacophoric group, pharmacophoric group due to two kinds of medicines is compatible in a molecule, therefore the compounds of this invention not only may possess the property of medicine of sulfa drugs and Beta-lactam medicine on pharmaceutical properties simultaneously, and each pharmacophoric group may have mutual synergy to strengthen anti-microbial activity, preliminary study shows, target compound has good anti-microbial activity to Pseudomonas aeruginosa, suitable with Pyocianil.
Embodiment
Technical scheme of the present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1
A kind of preparation method of 7-(4-is to azanol benzenesulfonyl)-3-desacetoxycephalosporanic acid, adopts following steps to obtain:
The NaHCO of 10ml water, 10ml acetone and 30ml0.76mol/L is added successively in four-hole bottle
3solution, after being cooled to-5 DEG C, then adds 2.14g7-ADCA (10mmol), reacts; Reaction is clarified to solution after half an hour, and holding temperature is constant, and slowly instillation 4.42g 4-Nitrobenzenesulfonyl chloride (0.02mol) in solution, filters after reaction 3h; At room temperature, the acetone in filtrate is steamed and removes, with 30ml ethyl acetate washing soln 3 times; Again solution is transferred in 200ml beaker, at 0 DEG C, in solution, add 50ml ethyl acetate, then drip the pH value of appropriate saturated oxalic acid solution regulator solution, when the pH of solution is 2-3, separate organic phase; By 10ml saturated common salt water washing organic phase 3 times, then use anhydrous sodium sulfate drying 6h; Filter after drying, concentrate, add sherwood oil precipitation solid; Obtain faint yellow solid (intermediate product) 0.9g, yield is 22%; Solid obtained above is dissolved in 50ml ethyl acetate, adds 50mg10%Pd-C, pass into hydrogen, under normal temperature, react 12h; Filter after reaction, filtration catalizer, filtrate condensing crystal, obtains 0.82g faint yellow solid, and yield is that 91.1%, HPLC mensuration shows that purity reaches 98.0%.FT-IR (KBr compressing tablet, u
maxcm
-1): 3700-3000 (OH+NH
+ 2), 1761 (C=O), 1387 (S=O);
1hNMR (DMSO-d
6, TMS, ppm): 1.98 (s, 3H, CH
3), 3.49 (d, H, CH2), 3.43 (d, H, CH
2), 4.88-4.89 (d, H, CH), 5.1-5.2 (t, H, CH), 6.85-6.88 (d, 2H, ar-H), 7.60-7.63 (d, 2H, ar-H), 8.64-8.67 (s, 2H, OH+NH), 8.9 (s, H, NH), 13 (s, H, COOH); EI-MS (m/e): 384.1 ([M]
-), 340 ([M]
--CO
2), 306 ([M]
--CO
2-H
2s).
The chemical structural formula of product is as follows:
Embodiment 2
A kind of preparation method of 6-(4-is to azanol benzenesulfonyl) penicillanic acid, adopts following steps to obtain:
The KHCO of 10ml water, 10ml acetone and 30ml0.76mol/L is added successively in four-hole bottle
3solution, after being cooled to-5 DEG C, then adds 2.14g6-APA (10mmol), reacts; Reaction is clarified to solution after half an hour, and holding temperature is constant, and slowly instillation 4.42g 4-Nitrobenzenesulfonyl chloride (0.02mol) in solution, filters after reaction 3h; At room temperature, the acetone in filtrate is steamed and removes, with 30ml ethyl acetate washing soln 3 times; Again solution is transferred in 200ml beaker, at 0 DEG C, in solution, add 50ml ethyl acetate, then drip the pH value of appropriate saturated oxalic acid solution regulator solution, when the pH of solution is 2-3, carry out separatory operation; The 10ml saturated common salt water washing 3 times of organic phase after separatory, then use anhydrous sodium sulfate drying 6h; Filter after drying, concentrate, add sherwood oil precipitation solid; Obtain faint yellow solid 2.9g (intermediate product), yield is 72.5%; Solid obtained above is dissolved in 50ml tetrahydrofuran (THF), adds 100mg10%Pd-C, pass into hydrogen, under normal temperature, react 12h; Filter after reaction, filtrate condensing crystal, obtains 2.72g faint yellow solid, and yield is that 93.8%, HPLC mensuration shows that purity reaches 98.0%.FT-IR (KBr compressing tablet u
maxcm
-1): 3700-3000 (OH+NH
2), 1776 (C=O), 1338 (S=O).
1hNMR (DMSO-d
6, TMS, ppm): 1.55 (s, 3H, CH
3), 1.46 (s, 3H, CH
3), 3.77 (s, H, CH), 4.2 (s, H, CH), 5.09-5.12 (t, H, CH), 5.29 (s, H, OH) 5.46-5.49 (t, H, CH), 7.14-7.16 (d, 2H, ar-H), 7.78-7.79 (d, 2H, ar-H), 8.85 (s, H, NH), 9.0 (s, H, NH), 12 (s, H, COOH) .EI-MS (m/e): 386 ([M-H]
-), 360 ([M-H-26]
-), 172 ([M-H-214]
-).
The chemical structural formula of product is as follows:
Two beta-lactam compound sterlings difference embodiment 1 and embodiment 2 obtained by analysis type HPLC detect (chromatographic column (150mm × 4.6mm/5um, Shim-packVP-ODSC18); Methanol-water system, gradient elution, determined wavelength 254nm, flow velocity 0.5ml/min, confirm that the purity of above-mentioned two beta-lactam compounds all reaches 98.0%.
Claims (4)
1. a preparation method for beta-lactam compound, is characterized in that, comprises the steps:
Step 1, by a certain amount of NaHCO
3or KHCO
3add in aqueous acetone solution;
Step 2,7-ADCA or 6-APA adding aequum in the solution of step 1 reacts, and adds the 4-Nitrobenzenesulfonyl chloride of aequum after reaction again in solution, fully filters after reaction, obtains filtrate;
Step 3, acetone in filtrate is steamed after removing, with the impurity in ethyl acetate washing soln removing solution, in solution, then instill the pH value of appropriate oxalic acid solution regulator solution again, by ethyl acetate, solution is extracted again, extraction liquid is carried out condensing crystal and obtains intermediate product;
Step 4, is dissolved in intermediate product in aprotic solvent, under Pd/C catalysis, passes into hydrogen and carries out hydrogenation reaction, filters, carry out condensing crystal, or add poor solvent to filtrate in filtrate after reaction, separates out solid, obtains required product;
The chemical structural formula of products therefrom is:
2. the preparation method of beta-lactam compound according to claim 1, it is characterized in that: in step 4, described aprotic solvent is ethyl acetate, tetrahydrofuran (THF), dioxane.
3. the preparation method of beta-lactam compound according to claim 1, it is characterized in that: in step 4, described poor solvent is sherwood oil, heptane, hexane, hexanaphthene or ether.
4. the beta-lactam compound that described in claim 1, beta-lactam compound preparation method obtains is preparing the application on anti Bacillus pyocyaneu Flugge medicine.
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|---|---|---|---|
| CN201410232591.5A CN103965214B (en) | 2014-05-28 | 2014-05-28 | A kind of beta-lactam compound and its preparation method and application |
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| CN201410232591.5A CN103965214B (en) | 2014-05-28 | 2014-05-28 | A kind of beta-lactam compound and its preparation method and application |
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|---|---|
| CN103965214A CN103965214A (en) | 2014-08-06 |
| CN103965214B true CN103965214B (en) | 2016-04-13 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2427206A1 (en) * | 1974-01-26 | 1975-07-31 | Ind Quimica Hispano Norteameri | 6-Sulphonamido-penicillanic acid derivs - prepd. by reacting 6-APA with an activated sulphonic acid |
| CN1035511A (en) * | 1988-02-03 | 1989-09-13 | 拜尔公司 | β-Nei Xiananleikangshengsu its preparation method and as medicine and the application in medicine |
-
2014
- 2014-05-28 CN CN201410232591.5A patent/CN103965214B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2427206A1 (en) * | 1974-01-26 | 1975-07-31 | Ind Quimica Hispano Norteameri | 6-Sulphonamido-penicillanic acid derivs - prepd. by reacting 6-APA with an activated sulphonic acid |
| CN1035511A (en) * | 1988-02-03 | 1989-09-13 | 拜尔公司 | β-Nei Xiananleikangshengsu its preparation method and as medicine and the application in medicine |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and antimicrobial activity of some penicillin and cephalosporin derivatives;Hashem, A. I.,et al.,;《Indian Journal of Chemistry》;19971231;第36卷(第2期);第196-198页 * |
| 新型β-内酰胺类抗生素及其特点;韩刚，等，;《东南大学学报（医学版）》;20080731;第27卷(第4期);第316-318页 * |
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Granted publication date: 20160413 Termination date: 20190528 |