CN100417654C - 2-benzene carboxylate penicillen compounds and its preparation method and application - Google Patents
2-benzene carboxylate penicillen compounds and its preparation method and application Download PDFInfo
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- CN100417654C CN100417654C CNB2004100003843A CN200410000384A CN100417654C CN 100417654 C CN100417654 C CN 100417654C CN B2004100003843 A CNB2004100003843 A CN B2004100003843A CN 200410000384 A CN200410000384 A CN 200410000384A CN 100417654 C CN100417654 C CN 100417654C
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Abstract
The present invention relates to a 2-phenylcarboxylate penicillene compound with antibacterial action, the structure of which is disclosed as follows. The compound comprises salt thereof and ester thereof. The compound has strong effect on gram-positive bacteria resistance, particularly MRSA activity resistance. The present invention also relates to a method for preparing the 2-phenylcarboxylate penicillene compound and an application for the compound in preparing antibacterial agents and antibacterials containing the compound as effective ingredients.
Description
Technical field
The present invention relates to have the 2-benzene carboxylic acid ester penem compound (form that comprises its salt and ester thereof) of anti-microbial effect and the preparation method of this compound.In addition, the invention still further relates to the application of this compounds in the preparation antiseptic-germicide, and contain the antibacterials of this compounds as effective constituent.
Background technology
In recent years; all kinds of microbiotic constantly are developed and come out; resistant organism at antiseptic-germicide also develops rapidly simultaneously; for example; methicillin-resistant staphylococcus aureus (MRSA), to the streptococcus aureus (MSSA) of methicillin-sensitivity etc., after these bacteriums contact antibacterials, morph by plasmid or karyomit(e) mediation; obtain resistance, caused new puzzlement to clinical treatment.Since finding MRSA in 1961, it has become modal pathogenic bacteria of nosocomial infection in the world wide, these drug-fast bacteria infections of the still difficult effectively control of the antibacterials of existing report, especially MRSA infects, because this bacterial strain not only has the intrinsic resistance to all kinds of β-Nei Xiananleikangshengsus, and can present the antibiotic multi-drug resistant of other class by obtaining other drug resistant gene, brought serious problems to clinical treatment.At present, vancomycin (Vancomycin) becomes treats the line medication that MRSA infects clinically, but because of having side effect, limited its application clinically, and, along with vancomycin in clinical widespread use, to its drug-fast MRSA with faecalis occurs and more obstinate thereupon.Antagonism MRSA has become clinically more stubborn problem.Thereby, press for and seek the new active microbiotic of strong anti-MRSA, also impel the industry worker to make great efforts to develop novel anti drug tolerant bacteria medicine, design and screening have the new antimicrobial drug of new chemical structure, new role mechanism or new role target position.
In seeking the active drug that can address the above problem, wide spectrum, novel ss-lactam antibiotics efficient, low toxicity are focus and focus place, and the research and development of carbapenem wherein and penem medicine are especially noticeable.On chemical structure, penems antibiotics and carbapenem antibiotics difference have been on 5 yuan of rings by sulfur carbon, compare with carbapenem, compounds has anti-microbial activity widely, and the anti-microbial activity of anaerobism gram-positive microorganism and most Gram-negative bacterias all is equal to or is better than cynnematin and Penicillin antibiotics.But its solid chemical compound of penems and ester type prodrug oral absorption are difficult for by the beta-lactam enzymic hydrolysis, and stable than carbapenem to dehydropeptidase-I (DHP-I) simultaneously, its anti Bacillus pyocyaneu Flugge activity is lower than carbapenem.
Penems antibiotics (formula 1) is first by the notion of the famous chemist Woodward of Harvard University based on penicillin and cynnematin fusion, in the penicillin skeleton, introduce two keys, increasing the beta-lactam reactivity, thereby improve the imagination of anti-microbial activity and design synthetic.
Developed the Faropenem (faropenem of listing, structure as shown in the formula) be the penem compound sodium salt, be that Laboratorios Biologicos Farmaceuticos (LABIOFAM) of Japanese Suntory company is synthetic, and with the new oral penems antibiotics of the common exploitation of Yamanouchi drugmaker, it is wide spectrum penems antibiotics medicine with very strong anti-microbial activity, especially to golden Portugal bacterium, penicillin-fast streptococcus pneumoniae, the anti-microbial activity of anerobes such as gram-positive microorganisms such as streptococcus faecium and bacteroides fragilis is apparently higher than existing cynnematin, anti-Gram-negative bacteria is active similar to oral cephalosporin, to the aerobic and anaerobism gram-positive microorganism except that Pseudomonas aeruginosa, negative bacterium demonstrates broad spectrum antibiotic activity.Faropenem belongs to beta-lactam on the structure, has tetrahydrofuran base to replace on the ring, is non-ester prototype absorption-type medicine, and stable to various β-Nei Xiananmeis, Resistant strain is few.Faropenem shows strong avidity to penicillin-binding protein (PBP-1,2,3), the intestinal bacteria PBP-2 of golden Portugal bacterium, show that its anti-microbial effect is strong, can (tinenam) compare with the carbapenem antibiotic of existing clinical use is safe, its distinguishing feature is stable to DHP-I, therefore can be individually dosed, and safe, especially high to the clearance rate of anerobe and gram-positive microorganism.Therefore, the strong effect wide-spectrum antibacterial effect of Faropenem is generally acknowledged, but it lacks effective bacteriostatic activity to MRSA.
Men-10700 (Menarini Spa), chemistry (5R by name, 6S-[(R)-the 1-hydroxyethyl]-2-(N-methyl G-NH2-N-methyl) penem-3-carboxylic acid, also be to study maximum penems antibiotics now, its broad spectrum antibiotic activity makes it to become effective microbiotic that the treatment anerobe causes infection.Its C
2The position is the amino acid derivative side chain, and the gram positive and negative bacterium beyond MRSA and the staphylococcus epidermidis is all demonstrated high anti-microbial activity.This compound is the most remarkable to the activity of MSSA and staphylococcus epidermidis, and anti-microbial activity is better than third generation cephalosporin; For gram negative strain MIC
90≤ 2mg/L, but very little to the MRSA curative effect.Because of Men-10700 the antagonism third generation cephalosporin Gram-negative bacteria aspect good antibacterial effect is arranged, developing its oral prodrugs type in the industry.
At present in the penems medicine of broad-spectrum antimicrobial,, all show, promptly MRSA is lacked effective bacteriostatic activity the broad-spectrum antibacterial action except that anti-MRSA as Faropenem etc.Therefore, seeking new anti-MRSA curative effect height, the little microbiotic of side effect becomes problem demanding prompt solution, people wish to develop a kind ofly have no drug resistance, effect is more outstanding, anti-microbial activity is higher microbiotic.
Summary of the invention
The inventor proposes the 2-benzene carboxylic acid ester penem compound that a class has anti-microbial effect through research and screening to the penems structure activity relationship, experimental results demonstrate that this compound especially has significant bacteriostatic activity to MRSA, has solved the problems referred to above.
The invention provides 2-benzene carboxylic acid ester penem compound, comprise the form of its salt and ester.
The invention provides the preparation method and the synthetic route of this 2-benzene carboxylic acid ester penem compound.
The present invention also provides the antibacterial application of 2-benzene carboxylic acid ester compounds, specifically, is that this compounds is at preparation antibiotics, the antibacterial application in the medicine of especially anti-MRSA.
The present invention also provides a kind of Tri-Biocin compositions that contains the formula I compound of significant quantity, the pharmaceutical composition of especially anti-MRSA.
2-benzene carboxylic acid ester penem compound provided by the invention is connected with 2-benzene carboxylic acid ester on the C-2 position of penem bicyclic mother nucleus, this compound structure is represented by general formula (I):
In the formula, n is 0,1 or 2; The R representative is connected one or more substituting groups on the phenyl ring, is selected from H, halogen atom, alkoxyl group, NO
2, CN or alkyl; R
1Be H, basic metal or the ester residue of hydrolysis in vivo.
The 2-benzene carboxylic acid ester penem compound of above-mentioned formula I structure provided by the invention has broad-spectrum antibacterial action, and especially the anti-microbial activity to MRSA is better than commercially available penems antibiotic medicine at present.
According to purpose of the present invention, by to the structure activity relationship of 2-benzene carboxylic acid ester penem compound and the research of anti-microbial effect, filter out the penem compound of the strongest formula I structure of anti-microbial effect, n is 0,1 or 2 in the preferred compound structure, and R is the alkoxyl group (OCH for example of H, F, Cl, Br, a 1-3 carbon
3, OC
2H
5), NO
2, CN or 1-3 carbon alkyl (CH for example
3, C2H
5).
In the The compounds of this invention, preferred n=0, i.e. 2-methyl benzoate penem compound.
In the The compounds of this invention, the optimum seeking site of substituent R be between the position or contraposition, especially be between the position, more preferably R is nitro, CN or the halogen atom of H, a position or para-orientation.
Part particular compound of the present invention is as shown in the table:
Above-claimed cpd provided by the invention especially has significant bacteriostatic activity to MRSA in its broad-spectrum antimicrobial, faecalis, responsive golden Portugal bacterium are also had good medicinal effect.
The present invention also provides and has contained the antibacterial combination of 2-benzene carboxylic acid ester penem compound as effective constituent, it contains the compound and the pharmaceutically useful auxiliary material of the formula I structure of pharmacy effective dose, comprise vehicle, thinner stablizer and correctives etc., mix according to the pharmaceutics ordinary method, make the form oral administration of tablet, capsule, granule, powder or syrup or with the non-oral administration of the form of injection.
Above-mentioned preparation can be by conventional pharmaceutical methods preparation.The available additive comprises that vehicle (can be carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative such as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose such as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative such as metasilicic acid magnalium; Phosphate derivative such as calcium phosphate; Carbonate derivative such as lime carbonate; Sulfate-derivatives such as calcium sulfate etc.), tackiness agent (for example gelatin, polyvinylpyrrolidone and polyoxyethylene glycol), disintegrating agent (for example derivatived cellulose such as Xylo-Mucine, polyvinylpyrrolidone), lubricant (for example talcum, Magnesium Stearate, spermaceti or boric acid etc.), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (for example Chang Yong sweeting agent and spices etc.), thinner and injection liquid be with solvent (for example water, ethanol and glycerine etc.).
The dosage of compound (I) is with differences such as patient age, sex, the state of an illness and difference.General adult's dosage is about 0.01-5000mg/ day, preferred 1-1000mg/ day, more preferably 5-500mg/ day.
A kind of as in the compounds of compound provided by the invention; can be synthesized out by proper method; for example can be to comprise making compound and selected benzene carboxylic acid compound generation esterification with general formula I I, and the process that removes protecting group, T in the formula
1And T
2Be respectively hydroxyl protecting group and carboxyl-protecting group.
According to synthetic method of the present invention, have the penem bicyclic mother nucleus (general formula I I) that methylol and the hydroxyl on parent nucleus and carboxyl all have protecting group by making 2, realize esterification 2 methylol dehydrations, slough protecting group then.This general formula compound II can be the commercially available prod, also can be that concrete grammar can be referring to Journal of MedicanalChemistry, 1992, Vol.35, No.101836-37 according to the synthetic intermediate product that obtains of document record.
In general formula compound II, 3 carboxyls and 6 methylols are protected before esterification, guarantee benzene carboxylic acid and 2 methylol dehydration esterifications, protecting group T
1And T
2Be chosen under the prerequisite that satisfies esterification and be not particularly limited, be easy to determine based on protected group characteristic, and the method for deprotection base is easy to realize to those skilled in the art.The concrete synthetic method according to the present invention, T
1Can be trialkyl silica class protecting group, for example tertiary butyl dimethylsilane (TBS) or trimethyl silane, T
2Be generally allyl-based protection or to nitrobenzyl (PNB) protecting group, and make esterification products remove T in proper order
1And T
2
In the preferred embodiment of the present invention, concrete building-up process can for: have substituent phenylformic acid, toluylic acid or phenylpropionic acid to be dissolved in (for example tetrahydrofuran (THF)) in the solvent on the above-mentioned reactant phenyl ring, add azo oxalic acid diethyl ester, add the tetrahydrofuran solution of formula II compound and triphen phosphorus then, (process a) to obtain esterification products after reacting completely; This esterification products is dissolved in organic solvent, remove hydroxyl protecting group (process b) through appropriate reaction, obtain intermediate product, this process can adopt acetonitrile to make solvent, add the dilute hydrochloric acid solution reaction and realize, also can adopt tetrahydrofuran (THF) to make solvent, at room temperature add acetate, tetrabutyl ammonium fluoride, reaction is 6 hours and finish about 50 ℃; Obtain intermediate product once more with behind the organic solvent dissolution; add four (triphen phosphorus) palladium continuously; the acetate matrix solution reaction of triphen phosphorus and 2 ethyl hexanoic acid sodium; solvent can be a haloalkane; methylene dichloride for example; esters solvent; ethyl acetate etc. for example; reaction system does not have raw material point back (removing carboxyl-protecting group) after testing, and extracting in water is through the further washing to the water layer product; can use methylene dichloride earlier; hexyl acetate is washed; wash drying again, purification process (process c) then with ether; promptly get purpose product of the present invention, the product that makes according to this embodiment method is a kind of sodium salt.
An embodiment of synthetic method of the present invention can realize according to following process: (R, n define with aforementioned)
a：
C
2H
5OCON＝NCOOC
2H
5，PPh
3
b：0.1M HCl，CH
3CN c：PPh
3，Pb(PPh
3)
4，CH
3CHC
2H
5(CH
2)
3COONa
In addition, the present invention also provides the application of 2-benzene carboxylic acid ester penem compound in the preparation antiseptic-germicide, and contains the antibacterial combination of 2-benzene carboxylic acid ester penem compound as effective constituent.
The bacteriostatic experiment result:
1. sample:
1) 63-78 product (synthetic sample)
2) Faropenem (Faropenem) (synthetic sample)
3) Sultacillin (medicine chemical industry company limited of Huangyan, Zhejiang Xinhua)
4) imipenum (Imipenem) (Mo Shadong)
5) meropenem (Meropenem) (Zhejiang Haizheng Pharmaceutical Co)
6) vancomycin (Vancomycin) (sigma)
2. prepare the antibiotic plate:
Drug sample is numbered, as table 1, according to required dose small amount of methanol hydrotropy, supply institute's required amount with distilled water, fully behind the dilution mixing, the preceding Guan Banliang of taking-up adds equivalent distilled water two-fold dilution and becomes 15 concentration, and each concentration is got the 1mL soup, after adding 19mL Mueller-Hinton Agar and training basic mixing, pour that plate is to be cooled to get final product into.Staphylococcus aureus and the experiment of excrement chain faecalis wherein include 5% sheep blood with above-mentioned training base, and other bacterium experiment is basic with the training of Mueller-Hinton Agar susceptibility.
3. plant the bacterium method:
Experimental bacteria is seeded in (10mL/ pipe) in the common nutrient broth, above-mentioned inoculation bacterium is put 37 ℃ hatch 18h, is diluted to 10 next day
6Use bacteria concentration as experiment, bacterium is added in the microwell plate, on the medicine plate of different concns, inoculate, wait to do, put 37 ℃ Celsius and hatch observations behind the 18h with the multiple spot inoculation method.
The MIC result of table 1 penem compound
| Drug | MIC(Ug/mL) | MSSA | MRSA | E.coli | P.aeruginosa | E.facialis |
| 63 | MIC50 MIC90 | 0.008 0.031 | 0.062 0.25 | 64 256 | 256 ＞256 | 2 16 |
| 64 | MIC50 MIC90 | 32 256 | 256 256 | 256 ＞256 | 256 ＞256 | 256 256 |
| 65 | MIC50 MIC90 | 0.008 0.008 | 0.062 0.5 | 64 128 | 256 ＞256 | 0.5 8 |
| 66 | MIC50 MIC90 | 0.008 0.008 | 0.008 1 | 128 256 | ＞256 ＞256 | 4 8 |
| 67 | MIC50 MIC90 | 0.031 0.062 | 0.25 1 | 64 128 | 256 ＞256 | 1 32 |
| 68 | MIC50 MIC90 | 0.008 0.008 | 0.25 1 | 16 64 | 256 ＞256 | 1 32 |
| 69 | MIC50 MIC90 | 0.031 0.25 | 0.5 2 | 256 256 | ＞256 ＞256 | 4 32 |
| 70 | MIC50 MIC90 | 0.031 0.062 | 0.5 2 | 64 128 | 256 ＞256 | 4 2 |
| 71 | MIC50 MIC90 | 0.062 0.25 | 1 2 | 64 128 | 256 ＞256 | 2 8 |
| 72 | MIC50 MIC90 | 0.008 0.008 | 0.125 0.5 | 128 256 | 256 ＞256 | 1 1 |
| 73 | MIC50 MIC90 | 0.008 0.25 | 0.25 2 | 64 128 | ＞256 ＞256 | 2 32 |
| 74 | MIC50 MIC90 | 0.008 0.031 | 0.125 1 | 128 ＞256 | 256 ＞256 | 2 16 |
| 75 | MIC50 MIC90 | 0.062 0.25 | 1 4 | 128 128 | 256 256 | 32 64 |
| 76 | MIC50 MIC90 | 0.031 0.062 | 0.25 0.5 | 64 128 | 128 128 | 1 4 |
| 77 | MIC50 MIC90 | 0.008 0.031 | 0.25 4 | 64 256 | 256 ＞256 | 2 8 |
| 78 | MIC50 MIC90 | 0.031 0.125 | 0.25 2 | 128 256 | 256 256 | 4 32 |
| Faropenem | MIC50 MIC90 | 0.062 0.125 | 128 256 | 0.5 4 | 256 ＞256 | 2 128 |
| Sultacilin | MIC50 MIC90 | 0.25 1 | 16 32 | 8 64 | 256 ＞256 | 4 64 |
| Imipenem | MIC50 MIC90 | 0.008 0.031 | 16 64 | 0.25 0.5 | 1 32 | 2 128 |
| Meropenem | MIC50 MIC90 | 0.031 0.25 | 16 32 | 0.016 0.031 | 0.125 2 | 4 128 |
| Vacomycin | MIC50 MIC90 | 0.5 1 | 1 2 | ＞256 ＞256 | ＞256 ＞256 | 2 4 |
According to above-mentioned formula (I) compound provided by the invention and pharmacological experiment result thereof, show that its structure activity relationship is as follows:
A. owing to 2 introducings of going up the benzene carboxylic acid ester side chain, the The compounds of this invention anti-microbial activity obviously improves;
B. the anti-microbial activity activity is along with the lengthening that prolongs side chain, and activity decreases, so n is 0,1 or 2 in formula (I) compound;
C. active do not have too big relation with substituent character, and R can be selected from H, F, Cl, Br, NO
2, CN or CH
3In arbitrary or a plurality of group, preferred R is an above-mentioned group;
D. on the phenyl ring between the penems antibiotics of different the position of substitution, the activity that a position replaces is apparently higher than ortho position and contraposition, and the ortho position is quite active with contraposition;
E. replacement is many more on the phenyl ring, and anti-microbial activity is poor more, therefore, and the preferred H of substituted radical, F, Cl, Br, NO on the phenyl ring of The compounds of this invention
2, CN or CH
3In arbitrary and position replace.
Conclusion:
1) to the golden Portugal of sensitivity bacterium, the 63-78 anti-microbial effect is parity with or superiority over faropenem, Sultacillin, meropenem, vacomycin.
2) all penem compounds all show the anti-microbial activity of good anti-MRSA, compare with the clinical application vancomycin, and anti-microbial activity at least quite or be better than vancomycin.
3) to faecalis, 63,65,67,68,71,72,73,74,76,77 anti-microbial activities and five kinds are with reference to medicine quite or be better than them.
Experimental result discloses, and in the microbiotic of existing anti-microbial type, is widely used in clinical most and by the known preferred Faropenem of the public, but the MIC of its anti-MRSA
90Be 256 μ g/ml, the MIC of the anti-MRSA of compound of the present invention
90Be 4 μ g/ml to the maximum, minimum (position replaces) is 0.25 μ g/ml, compares drug effect with Faropenem and improved 64-1000 doubly, and antibacterial effect obviously is better than other similar medicines.
In sum, the 2-benzene carboxylic acid ester penem compound that designs and synthesizes, especially 2-benzene carboxylic acid methyl esters penem compound (except that 64) all has higher anti-microbial activity to gram-positive microorganism MSSA and faecalis, all demonstrates good antibacterial effect for MRSA especially.
Embodiment
Embodiment 1 (5R, 6S)-2-(Chlorodracylic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 31
Take by weighing Chlorodracylic acid (0.596g, 3.811mmol) be dissolved in the 6mL tetrahydrofuran (THF), add azo oxalic acid diethyl ester (0.664g, 3.811mmol), slowly add 29 (1.264g then, 3.176mmol) and three stupid phosphorus (281.00, tetrahydrofuran solution 3.811mmol), color gradually by orange become light yellow or colourless.Behind the reaction 8h, TLC detects, and reacts completely.After removing tetrahydrofuran (THF) under reduced pressure under the normal temperature, add hexyl acetate and extract.Use saturated sodium bicarbonate and washing respectively, anhydrous sodium sulfate drying concentrates.Hexyl acetate: methylene dichloride (1: 4) wash-out, collect component.Get white solid 31 (1.36g, 80%).
m.p.101-102℃.
1H NMR(CDCl
3)δ8.05(dd，J＝6.9Hz，2H，Ph)，7.47(dd，2H，J＝8.7Hz，Ph)，5.92(m，1H，
CH＝CH
2)，5.75-5.62(m，1H，H5and CH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.79-4.68(m，2H，O
CH 2CH＝CH
2)，4.47-4.20(m，1H，CHOSi)，2.72(d，J＝3.9Hz，H6)，1.28(d，J＝6.9Hz，
CH 3-CH)，0.87(s，9H)，0.08(s，6H).MS(FAB)m/z 538(M+H
+)，537(M)。
Embodiment 2 (5R, 6S)-2-(m-methoxybenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 32
With m-methoxybenzoic acid and 29 is raw material, and operation is with 31.Get faint yellow solid, yield 87%.
m.p.78-79℃.
1H NMR(CDCl
3)：δ7.85(d，J＝7.8Hz，1H，Ph)，7.50(m，1H，Ph)，6.99(m，2H，Ph)，5.92(m，1H，
CH＝CH
2)，5.72-5.60(m，2H，H5 andCH
2CH＝
CH)，5.43-5.23(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.72(m，2H，O
CH 2CH＝CH
2)，4.23(m，1H，
CHOSi)，2.85(s，3H，-O
CH 3)，1.25(d，J＝6.9Hz，3H，
CH 3-CH)，0.87(s，9H)，0.08(s，6H).FAB-MS：m/z 534(M+H
+)。
Embodiment 3 (5R, 6S)-2-(fluorobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 33
With a fluorobenzoic acid and 29 is raw material, and operation is with 31.Get weak yellow liquid, yield 79%.
1H NMR(CDCl
3)：δ7.86(m，1H，Ph)，7.73(d，J＝8.7Hz，1H，Ph)，7.44(m，1H，Ph)，7.31(m，1H，Ph)，5.94(m，1H，
CH＝CH
2)，5.76-5.63(m，2H，H5 andCH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.71(m，2H，O
CH 2CH＝CH
2)，4.23(m，1H，CHOSi)，3.73(d，J＝3.9Hz，1H，H6)，1.27(m，3H，
CH 3-CH)，0.87(s，9H)，0.08(s，6H).FAB-MS：m/z 520(M-H
+)。
Embodiment 4 (5R, 6S)-2-(M-NITROBENZOIC ACID) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 34
With M-NITROBENZOIC ACID and 29 is raw material, and operation is with 31.Get colourless liquid, yield 91%.
1H NMR(CDCl
3)：δ8.87(m，1H，Ph)，8.46(m，2H，Ph)，7.69(m，1H，Ph)，5.95(m，1H，
CH＝CH
2)，5.83-5.65(m，2H，H5and CH
2CH＝
CH)，5.45-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.76(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.74(m，1H，H6)，1.23(d，J＝6.3Hz，3H，
CH 3-H)，0.87(s，9H)，0.07(s，6H).FAB-MS：m/z 547(M-H
+)。
Embodiment 5 (5R, 6S)-2-(phenylpropionic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 35
With phenylpropionic acid and 29 is raw material, and operation is with 31.Get colourless liquid, yield 87%.
1H NMR(CDCl
3)：δ7.29-7.19(m，5H，Ph)，5.92(m，1H，
CH＝CH
2)，5.56(d，J＝1.2Hz，1H，H5)，5.51-5.36(m，2H，CH
2CH＝
CH 2)，5.26-5.08(m，2H，
CH 2OCO)，4.70(m，2H，O
CH 2CH＝CH
2)，4.23(m，1H，CHOSi)，3.69(m，1H，H6)，2.97(m，2H，OC
CH 2CH
2)，2.69(m，2H，OCCH
2 CH 2)，1.23(d，J＝5.7Hz，3H，
CH 3-CH)，0.88(s，9H)，0.07(s，6H).FAB-MS：m/z 530(M-H
+)。
Embodiment 6 (5R, 6S)-2-(toluylic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 36
With toluylic acid and 29 is raw material, and operation is with 31.Get white solid, yield 93%.
m.p.67-69℃.
1H NMR(CDCl
3)：δ7.30(m，5H，Ph)，5.90(m，1H，
CH＝CH
2)，5.56-5.48(m，2H，H5 and CH
2CH＝
CH)，5.41-5.08(m，3H，CH
2CH＝
CH and
CH 2OCO)，4.68(m，2H，O
CH 2CH＝CH
2)，4.22(m，1H，CHOSi)，3.67(m，3H，H6and OC
CH 2Ph)，1.24(d，J＝8.7Hz，3H，
CH 3-CH)，0.88(s，9H)，0.07(s，6H).FAB-MS：m/z 516(M-H
+)。
Embodiment 7 (5R, 6S)-2-(anisic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 37
With anisic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 89%.
m.p.73-75℃.
1H NMR(CDCl
3)δ8.00(d，J＝9.9Hz，2H，Ph)，6.93(d，J＝9.0Hz，2H，Ph)，5.92(m，1H，
CH＝CH
2)，5.72-5.60(m，2H，H5and CH
2CH＝
CH)，5.43-5.30(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.72(m，2H，O
CH 2CH＝CH
2)，4.23(m，1H，CHOSi)，3.86(s，3H，O
CH 3)，3.71(d，J＝4.8Hz，1H，H6)，1.21(d，J＝6.9Hz，3H，
CH 3-H)，0.87(s，9H)，0.06(s，6H).FAB-MS：m/z534(M+H
+))，532(M-H
+)。
Embodiment 8 (5R, 6S)-2-(parafluorobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 38
With parafluorobenzoic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 86%.
m.p.100-101.5℃.
1H NMR(CDCl
3)：δ8.07(m，2H，Ph)，7.12(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.75-5.62(m，2H，H5 and CH
2CH＝
CH)，5.45-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.74(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.73(dd，J＝1.5，4.5Hz，1H，H6)，1.23(d，J＝6.3Hz，3H，
CH 3-H)，0.88(s，9H)，0.08(s，6H).FAB-MS：m/z 522(M+H
+)。
Embodiment 9 (5R, 6S)-2-(pentafluorobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 39
With pentafluorobenzoic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 80%.
m.p.110-111℃。
1H NMR(CDCl
3)：δ5.92(m，1H，
CH＝CH
2)，5.80(d，J＝14.7Hz，1H，CH
2-CH＝
CH)，5.64(s，1H，H5)，5.44-5.24(m，3H，CH
2CH＝
CHand，
CH 2OCO)，4.72(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.75(m，1H，H6)，1.23(d，J＝5.7Hz，3H，
CH 3-H)，0.88(s，9H)，0.07(s，6H).FAB-MS：m/z592(M-H
+)。
Embodiment 10 (5R, 6S)-2-(parabromobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 40
With parabromobenzoic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 86%.
m.p.125-127℃.
1H NMR(CDCl
3)：δ7.90(d，J＝8.7Hz，2H，Ph)，7.59(d，J＝8.7Hz，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.75-5.62(m，2H，H5 andCH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2c-CH＝
CH)，4.73(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.72(dd，J＝1.5，4.5Hz，1H，H6)，1.22(d，J＝6.6Hz，3H，
CH 3-H)，0.87(s，9H)，0.07(s，6H).FAB-MS：m/z 582(M+H
+)。
Embodiment 11 (5R, 6S)-2-(o-fluorobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 41
With o-fluorobenzoic acid and 29 is raw material, and operation is with 31.Get white solid.Yield 94%.
m.p.81.5～82.5℃.
1H NMR(CDCl
3)：δ8.00(m，1H，Ph)，7.58(m，1H，Ph)，7.22(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.78-5.62(m，2H，H5and CH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.72(m，2H，O
CH 2CH＝CH
2)，4.23(m，1H，CHOSi)，3.73(dd，J＝2.1，4.5Hz，1H，H6)，1.23(d，J＝6.3Hz，3H，
CH 3-H)，0.88(s，9H)，0.08(s，6H).FAB-MS：m/z 522(M+H
+)。
Embodiment 12 (5R, 6S)-2-(o-methoxybenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 42
With o-methoxybenzoic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 87%.
m.p.62-64℃.
1H NMR(CDCl
3)：δ7.94(m，1H，Ph)，7.41(m，1H，Ph)，7.26(m，2H，Ph)，5.92(m，1H，
CH＝CH
2)，5.74-5.61(m，2H，H5 and CH
2CH＝
CH)，5.45-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.73(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.72(dd，J＝1.5，4.5Hz，1H，H6)，2.62(s，3H，
CH 3)，1.22(d，J＝6.3Hz，3H，
CH 3-CH)，0.86(s，9H)，0.07(s，6H).FAB-MS：m/Z 516(M-H
+)。
Embodiment 13 (5R, 6S)-2-(paracyanobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 43
With paracyanobenzoic acid and 29 is raw material, and operation is with 31.Get white crystal, yield 76%.
m.p.100～102℃.
1H NMR(CDCl
3)：δ8.14(d，J＝7.8Hz，2H，Ph)，7.76(d，J＝7.8Hz，2H，Ph)，5.91(m，1H，
CH＝CH
2)，5.79-5.63(m，2H，H5andCH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.73(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.73(d，J＝3.9Hz，1H，H6)，1.22(d，J＝6.0Hz，3H，
CH 3-H)，0.87(s，9H)，0.07(s，6H).FAB-MS：m/z 528(M)。
Embodiment 14 (5R, 6S)-2-(p-nitrobenzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 44
With p-nitrobenzoic acid and 29 is raw material, and operation is with 31.Get white solid, yield 95%.
m.p.152-154℃.
1H NMR(CDCl
3)：δ8.30(m，4H，Ph)，5.92(m，1H，
CH＝CH
2)，5.81-5.64(m，2H，H5 and CH
2CH＝
CH)，5.45-5.25(m，3H，
CH 2OCOand CH
2-CH＝
CH)，4.73(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.74(dd，J＝1.8，4.5Hz，1H，H6)，1.23(d，J＝6.3Hz，3H，
CH 3-H)，0.87(s，9H)，0.08(s，6H).FAB-MS：m/z 549(M+H
+)，547(M-H
+)。
Embodiment 15 (5R, 6S)-2-(o-Carboxynitrobenzene) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 45
With o-Carboxynitrobenzene and 29 is raw material, and operation is with 31.Get colourless liquid, yield 79%.
1H NMR(CDCl
3)：δ7.95(m，1H，Ph)，7.77(m，1H，Ph)，7.68(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.77-5.63(m，2H，H5and CH
2CH＝
CH)，5.44-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.72(m，2H，O
CH 2CH＝CH
2)，3.73(dd，J＝2.1，4.2Hz，1H，H6)，1.22(d，J＝6.3Hz，3H，
CH 3CH)，0.87(s，9H)，0.06(s，6H).FAB-MS：m/z 547(M-H
+)。
Embodiment 16 (5R, 6S)-2-(0-chloro-benzoic acid) methyl esters-6-[(1R)-the 1-tertiary butyl-2-dimethyl silica ethyl]-penem-3-allyl carboxylate 46
With 0-chloro-benzoic acid and 29 is raw material, and operation is with 31.Get white solid, yield 81%.
m.p.130-131℃.
1H NMR(CDCl
3)：δ8.07(m，2H，Ph)，7.12(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.75-5.62(m，2H，H5 and CH
2CH＝
CH)，5.45-5.24(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.74(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.73(dd，J＝1.5，4.5Hz，1H，H6)，1.23(d，J＝6.3Hz，3H，
CH 3-H)，0.88(s，9H)，0.08(s，6H).FAB-MS：m/z 399(M+H
+)。
Embodiment 17 (5R, 6S)-2-(Chlorodracylic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 47
The diluted hydrochloric acid aqueous solution 45mL that adds 0.1N in the acetonitrile solution of 31 (1.5mmol), behind the stirring reaction 12h, TLC detects and reacts completely.In reaction mixture, add 8% aqueous sodium hydroxide solution 4.5mL.Be concentrated into seldom volume.Add hexyl acetate, after giving a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous sodium sulfate drying.Vacuum boils off hexyl acetate, hexyl acetate: methylene dichloride (4: 1,1: 1) wash-out, collect the product component, and obtain white solid, yield 67%.
m.p.131-132℃.
1H NMR(CDCl
3)：δ7.98(d，J＝7.8Hz，2H，Ph)，7.46(d，H＝10.8，2H，Ph)，6.00-5.88(m，1H，
CH＝CH
2)，5.72-5.65(m，2H，H5 andCH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.73-4.66(m，2H，O
CH 2CH＝CH
2)，4.29-4.21(m，1H，CHOSi)，3.77(d，J＝6.6Hz，1H，H6)，1.34(d，J＝6.9Hz，3H，
CH 3-H).FAB-MS：m/z 424(M+H
+)。
Embodiment 18 (5R, 6S)-2-(o-methoxybenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 48
32 to be raw material, operation is with 47.Get white crystal, yield 81%.
m.p.94-95℃.
1H NMR(CDCl
3)：δ7.85(m，1H，Ph)，7.51(m，1H，Ph)，6.99(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.70-5.63(m，2H，H5 and CH
2CH＝
CH)，5.45-5.25(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.75(m，2H，O
CH 2CH＝CH
2)，4.22(m，1H，CHOSi)，3.76(d，J＝1.5Hz，1H，H6)，1.35(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/z 420(M+H
+)。
Embodiment 19 (5R, 6S)-2-(fluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 49
33 to be raw material, operation is with 47.Get faint yellow solid, yield 85%.
m.p.103-104℃.
1H NMR(CDCl
3)：δ7.84(d，J＝7.8Hz，1H，Ph)，7.72(d，J＝9.3，1H，Ph)，7.44(m，1H，Ph)，7.30(m，1H，Ph)，5.95(m，1H，
CH＝CH
2)，5.73-5.66(m，2H，H5and CH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.76(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.78(d，J＝6.3Hz，1H，H6)，1.34(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/z 407(M
+)。
Embodiment 20 (5R, 6S)-2-(M-NITROBENZOIC ACID) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 50
34 to be raw material, operation is with 47.Get white crystal, yield 82%.
m.p.160-161℃.
1H NMR(CDCl
3)：δ8.87(s，1H，Ph)，8.47-8.37(m，2H，Ph)，7.69(m，1H，Ph)，5.98(m，1H，
CH＝CH
2)，5.80-5.67(m，2H，H5and CH
2CH＝
CH)，5.46-5.27(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.80(m，2H，O
CH 2CH＝CH
2)，4.26(m，1H，CHOSi)，3.81(m，1H，H6)，1.35(d，J＝5.7Hz，3H，
CH 3-H).FAB-MS：m/z 434(M
+)。
Embodiment 21 (5R, 6S)-2-(phenylpropionic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 51
35 to be raw material, operation is with 47.Get white crystal.Yield 90%.
m.p.77-78℃.
1H NMR(CDCl
3)：δ7.31(m，5H，Ph)，5.94(m，1H，
CH＝CH
2)，5.70(s，1H，H5)，5.60-5.28(m，2H，CH
2CH＝
CH 2)，5.28-5.09(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.79(m，2H，O
CH 2CH＝CH
2)，4.26(m，1H，CHOSi)，3.73(m，1H，H6)，2.97(m，2H，OC
CH 2CH
2)，2.74(m，2H，OCCH
2 CH 2)，1.34(d，J＝3.6Hz，3H，
CH 3-H).FAB-MS：m/z 417(M
+)。
Embodiment 22 (5R, 6S)-2-(toluylic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 52
36 to be raw material, operation is with 47.Get yellow crystals.Yield 86%.
m.p.71-73℃.
1H NMR(CDCl
3)：δ7.30(m，5H，Ph)，5.93(m，1H，
CH＝CH
2)，5.59-5.10(m，5H，H5，CH
2CH＝
CH 2，
CH 2OCO)，4.73(m，2H，CH
2-CH＝
CH)，4.22(m，1H，CHOSi)，3.73(d，J＝6.9Hz，1H，H6)，3.67(s，2H，OC
CH 2)，1.34(d，J＝6.9Hz，3H，
CH 3-H).FAB-MS：m/z 403(M
+)。
Embodiment 23 (5R, 6S)-2-(anisic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 53
37 to be raw material, operation is with 47.Get white crystal.Yield 92%.
m.p.89-90℃.
1H NMR(CDCl
3)：δ8.00(m，2H，Ph)，6.92(m，2H，Ph)，5.92(m，1H，
CH＝CH
2)，5.69-5.63(m，2H，H5 and CH
2CH＝
CH)，5.45-5.25(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.73(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.86(m，1H，H6)，3.75(m，1H，H6)，1.34(d，J＝5.7Hz，3H，
CH 3-CH).FAB-MS：m/z420(M
++H)。
Embodiment 24 (5R, 6S)-2-(parafluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 54
38 to be raw material, operation is with 47.Get white crystal.Yield 86%.
m.p.103-104℃.
1H NMR(CDCl
3)：δ8.07(m，2H，Ph)，7.13(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.72-5.65(m，2H，H5 and CH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.78(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.77(dd，J＝2.1，6.9Hz，1H，H6)，1.35(d，J＝6.9Hz，3H，
CH 3-H).FAB-MS：m/z407(M+H
+)。
Embodiment 25 (5R, 6S)-2-(pentafluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 55
39 to be raw material, operation is with 47.Get white solid.Yield 89%.
m.p.164-166℃.
1H NMR(CDCl
3)：δ5.95(m，1H，
CH＝CH
2)，5.76(d，J＝15Hz，1H，CH
2CH＝
CH)，5.67(d，J＝1.8Hz，1H，H5)，5.45-5.26(m，3H，CH
2-CH＝
Ch and
CH 2OCO)，4.77(m，2H，O
CH 2CH＝CH
2)，4.26(m，1H，CHOSi)，3.78(m，1H，H6)，1.35(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/Z 268(M-C
6H
5COO
+)。
Embodiment 26 (5R, 6S)-2-(parabromobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 56
40 to be raw material, operation is with 47.Get white crystal.Yield 82%.
m.p.138-140℃.
1H NMR(CDCl
3)：δ7.89(d，J＝8.1Hz，2H，Ph)，7.59(d，J＝8.7Hz，2H，Ph)，5.96(m，1H，
CH＝CH
2)，5.72-5.64(m，2H，H5andCH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.78(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.77(d，J＝6.0Hz，1H，H6)，1.34(d，J＝6.9Hz，3H，
CH 3-CH).FAB-MS：m/z 467(M
+)，469(M
++2)。
Embodiment 27 (5R, 6S)-2-(o-fluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 57
41 to be raw material, operation is with 47.Get colourless liquid.Yield 81%.
1H NMR(CDCl
3)：δ7.95(m，1H，Ph)，7.55(m，1H，Ph)，7.19(m，2H，Ph)，5.94(m，1H，
CH＝CH
2)，5.74-5.65(m，2H，H5 and CH
2CH＝
CH)，5.45-5.25(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.77(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.77(m，1H，H6)，1.34(d，J＝6.9Hz，3H，
CH 3-CH).FAB-MS：m/z 407(M
+)。
Embodiment 28 (5R, 6S)-2-(o-toluic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 58
42 to be raw material, operation is with 47.Get white crystal.Yield 87%.
m.p.110-111℃.
1H NMR(CDCl
3)：δ7.93(d，J＝7.8Hz，1H，Ph)，7.42(m，1H，Ph)，7.25(m，2H，Ph)，5.98(m，1H，
CH＝CH
2)，5.71-5.64(m，2H，H5 andCH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.75(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.77(d，J＝6.6Hz，1H，H6)，2.61(s，3H，
CH 3)，1.34(d，J＝5.7Hz，3H，
CH 3-H).FAB-MS：m/z 403(M
+)。
Embodiment 29 (5R, 6S)-2-(p-nitrobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 59
43 to be raw material, operation is with 47.Get white crystal.Yield 79%.
m.p.165-166℃.
1H NMR(CDCl
3)：δ8.15(d，J＝7.8Hz，2H，Ph)，7.77(d，J＝7.8Hz，2H，Ph)，5.95(m，1H，
CH＝CH
2)，5.76-5.66(m，2H，H5 andCH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.81(m，2H，O
CH 2CH＝CH
2)，4.26(m，1H，CHOSi)，3.78(d，J＝6.0Hz，1H，H6)，1.35(d，J＝6.0Hz，3H，
CH 3-H).FAB-MS：m/z 415(M+H
+)。
Embodiment 30 (5R, 6S)-2-(p-nitrobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 60
44 to be raw material, operation is with 47.Get white solid.Yield 83%.
m.p.172-174℃.
1H NMR(CDCl
3)：δ8.26(m，4H，Ph)，5.92(m，1H，
CH＝CH
2)，5.78-5.67(m，2H，H5 and CH
2CH＝
CH)，5.45-5.27(m，3H，
CH 2OCOand CH
2-CH＝
CH)，4.76(m，2H，O
CH 2CH＝CH
2)，4.26(m，1H，CHOSi)，3.78(d，J＝7.8Hz，1H，H6)，1.35(d，J＝6.0Hz，3H，
CH 3-H).FAB-MS：m/z 433(M-H
+)。
Embodiment 31 (5R, 6S)-2-(o-Carboxynitrobenzene) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 61
45 to be raw material, operation is with 47.Get light yellow crystal.Yield 88%.
m.p.130-133℃.
1H NMR(CDCl
3)：δ7.95(m，1H，Ph)，7.79-7.66(m，3H，Ph)，5.96(m，1H，
CH＝CH
2)，5.75-5.65(m，2H，H5and CH
2CH＝
CH)，5.45-5.26(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.75(m，2H，O
CH 2CH＝CH
2)，4.24(m，1H，CHOSi)，3.77(m，1H，H6)，1.34(d，J＝5.7Hz，3H，
CH 3-CH).FAB-MS：m/z434(M
+)。
Embodiment 32 (5R, 6S)-2-(0-chloro-benzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-allyl carboxylate 62
46 to be raw material, operation is with 47.Get white solid.Yield 82%.
m.p.145-146℃.
1H NMR(CDCl
3)：δ7.88(d，J＝6.6Hz，1H，Ph)，7.51-7.31(m，3H，Ph)，5.99(m，1H，
CH＝CH
2)，5.74-5.65(m，2H，H5and CH
2CH＝
CH)，5.48-4.84(m，3H，
CH 2OCO and CH
2-CH＝
CH)，4.72(m，2H，O
CH 2CH＝CH
2)，4.25(m，1H，CHOSi)，3.76(dd，J＝1.5，6.6Hz，1H，H6)，1.37(d，J＝7.2Hz，3H，
CH 3-H).FAB-MS：m/z 424(M+H
+)。
Embodiment 33 (5R, 6S)-2-(Chlorodracylic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 63
47 (1.25mmol) are dissolved in the 1.5mL methylene dichloride, add four (triphen phosphorus) palladiums (0.0125mmol), the hexyl acetate solution 1.5mL of triphen phosphorus (0.0625mmol) and 2 ethyl hexanoic acid sodium (1.43mmol) under the room temperature continuously.TLC detects behind the stirring reaction 1h, has not had the raw material point.Add the 2mL water extraction, water layer is washed with methylene dichloride and hexyl acetate, washes with ether.Lyophilize obtains yellow solid.With macropore tree reversed-phase column purifying, gradient elution: water; Water: acetone (95: 5; 9: 1; 4: 1; 1: 1); Acetone.The obtained component lyophilize obtains white solid 63, yield 72%.
1H NMR(CDCl
3)：δ8.02(d，J＝5.1Hz，2H，Ph)，7.53(d，J＝5.1Hz，2H，Ph)，5.80(d，J＝8.4Hz，1H，H5)，5.61and 5.40(m，2H，
CH 2OCO)，4.11(m，1H，CHOSi)，3.66(d，J＝4.2，1H，H6)，1.30(d，J＝3.9Hz，3H，
CH 3-H).IR(KBr)v
maxcm
-1：1770(β-lactam C＝O)，1724(OC＝O)，1595，1489.FAB-MS：m/z 428(M
++Na)。
Embodiment 34 (5R, 6S)-2-(o-methoxybenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 64
48 to be raw material, operation is with 47.Get white solid, yield 67%.
1H NMR(CDCl
3)：δ7.77(d，J＝4.2Hz，1H，Ph)，7.54(m，1H，Ph)，7.11(d，J＝5.1Hz，1H，Ph)，6.98(m，1H，Ph)，5.72(d，J＝9.0Hz，1H，
CHOCO)，5.63(s，1H，H5)，5.42(d，J＝9.0Hz，1H，
CHOCO)，4.12(m，1H，CHOSi)，3.88(s，3H，OCH
3)，3.78(d，J＝3.9Hz，1H，H6)，1.30(d，J＝3.9Hz，3H，
CH 3-H).
13CNMR(D
2O)δ：175.80(COONa)，166.95(C＝O)，160.97(C＝O)，145.51(C＝C)，127.91(C＝C)，135.46，132.81，127.92，121.38，120.11，113.30(6C，Ph)，71.67(2′-C)，68.42(OCH
2)，66.16(C
6)，63.80(1′-C)，56.38(C
5)，21.71(CH
3)；IR(KBr)v
maxcm
- 1：1759(β-lactam C＝O)，1736(OC＝O)，1601，1491.FAB-MS：m/z 402(M+H
+)。
Embodiment 35 (5R, 6S)-2-(fluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 65
49 to be raw material, operation is with 47.Get faint yellow solid, yield 64%.
1H NMR(CDCl
3)：δ7.50(d，J＝7.8Hz，1H，Ph)，7.59(m，1H，Ph)，7.47-7.40(m，1H，Ph)，7.33-7.27(m，1H，Ph)，5.70(d，J＝14.7Hz，1H，
CHOCO)，5.56(d，J＝1.2Hz，1H，H5)，5.36(d，J＝14.7Hz，1H，
CHOCO)，4.02(m，1H，CHOSi)，1.70(dd，J＝1.2，6.6Hz，1H，H6)，1.21(d，J＝10.8Hz，3H，
CH 3-H).
13CNMR(D
2O)δ：175.72(COONa)，165.82(C＝O)，165.54(C＝O)，162.30(C＝C)，144.96(C＝C)，133.09，132.99，128.11，126.60，121.30，117.2(6C，Ph)，71.73(C
6)，66.08(
CHOH)，63.84(C
5)，62.12(CH
2O)，21.67(CH
3)；FAB-MS：m/z390(M+H
+)。
Embodiment 36 (5R, 6S)-2-(M-NITROBENZOIC ACID) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 66
50 to be raw material, operation is with 47.Get white solid, yield 78%.
1H NMR(CDCl
3)：δ8.71(s，1H，Ph)，8.41(d，J＝6.9Hz，1H，Ph)，8.31(d，J＝7.8Hz，1H，Ph)，7.67(m，1H，Ph)，5.79(d，J＝14.7Hz，1H，
CHOCO)，5.56(d，J＝1.5Hz，1H，H5)，5.40(d，J＝14.7Hz，1H，
CHOCO)，4.04(m，1H，CHOSi)，3.67(d，J＝6.9Hz，1H，H6)，1.20(d，J＝6.6Hz，3H，
CH 3-H).IR(KBr)v
maxcm
-1：1763(β-lactam C＝O)，1732(OC＝O)。
Embodiment 37 (5R, 6S)-2-(phenylpropionic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 67
51 to be raw material, operation is with 47.Get faint yellow solid, yield 54%.
1H NMR(CDCl
3)：δ7.29-7.17(m，5H，Ph)，5.56(d，J＝6.0Hz，1H，H5)，5.52and 5.18(d，J＝8.7Hz，
CH 2OCO)，4.11(m，1H，CHOSi)，3.73(d，J＝3.9Hz，1H，H6)，2.94(m，2H，OCCH
2)，2.65(m，2H，OCCH
2 CH 2)，1.30(d，J＝7.8Hz，3H，
CH 3-H)。
Embodiment 38 (5R, 6S)-2-(toluylic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 68
52 to be raw material, operation is with 47.Get faint yellow solid, yield 72%.
1H NMR(CDCl
3)：δ7.20(m，5H，Ph)，5.48(m，2H，H5 and
CHOCO)，5.10(d，J＝14.4Hz，1H，
CHOCO)，4.01(m，1H，CHOSi)，3.60(s，3H，H6 and OC-CH
2-Ph)，1.30(d，J＝3.9Hz，3H，
CH 3-H).FAB-MS：m/z 386(M+H
+)。
Embodiment 39 (5R, 6S)-2-(anisic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 69
53 to be raw material, operation is with 47.Get white solid, yield 65%.
1H NMR(CDCl
3)：δ7.91(m，2H，Ph)，6.90(m，2H，Ph)，5.62-5.18(3H，H5and
CH 2OCO)，4.13(m，1H，CHOSi)，3.80(s，3H，OCH
3)，3.23(m，1H，H6)，1.30(d，J＝3.9Hz，3H，
CH 3-H).FAB-MS(m/z)：402(M+H
+)。
Embodiment 40 (5R, 6S)-2-(parafluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 70
54 to be raw material, operation is with 47.Get faint yellow solid, yield 79%.
1H NMR(CDCl
3)：δ8.03-7.95(m，2H，Ph)，7.19-7.07(m，2H，Ph)，5.70(d，J＝14.7，1H，
CHOCO)，5.60(s，1H，H5)，5.35(d，J＝14.7Hz，1H，
CHOCO)，4.11-3.99(m，1H，CHOSi)，3.64(d，J＝1.2Hz，1H，H6)，1.21(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/z 390(M+H
+)。
Embodiment 41 (5R, 6S)-2-(pentafluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 71
55 to be raw material, operation is with 47.Get white solid, yield 81%.
1H NMR(CDCl
3)：δ5.83(d，J＝14.1Hz，1H，
CHOCO)，5.54(d，J＝1.2Hz，1H，H5)，5.37(d，J＝14.1Hz，1H，
CHOCO)，4.04(m，1H，CHOSi)，3.62(dd，J＝1.2，7.2Hz，H6)，1.22(d，J＝6.3Hz，3H，
CH 3-H)；FAB-MS：m/z 462(M+H
+)。
Embodiment 42 (5R, 6S)-2-(parabromobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 72
48 to be raw material, operation is with 47.Get white solid, yield 58%.
1H NMR(D
2O)：δ7.83(d，J＝8.4Hz，2H，Ph)，7.52(d，J＝8.7Hz，2H，Ph)，5.70(d，J＝14.7Hz，1H，
CHOCO)，5.55(d，J＝1.2H，1H，H5)，5.35(d，J＝14.7Hz，1H，
CHOCO)，4.03(m，1H，CHOSi)，3.67(dd，J＝1.2，6.9Hz，1H，H6)，1.21(d，J＝6.3Hz，3H，
CH 3-H).IR(KBr)v
maxcm
-1：1766(β-1actam C＝O)，1718(OC＝O).FAB-MS：m/z 450(M+H
+)。
Embodiment 43 (5R, 6S)-2-(o-fluorobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 73
57 to be raw material, operation is with 47.Get white solid, yield 77%.
1H NMR(D
2O)：δ7.90-7.84(m，1H，Ph)，7.60-7.53(m，1H，Ph)，7.24-7.10(m，2H，Ph)，5.65(d，J＝18.6Hz，1H，H5)，5.55and 5.35(m，2H，
CH 2OCO)，4.12-3.99(m，1H，CHOSi)，3.66(d，J＝5.7Hz，1H，H6)，1.21(d，J＝6.9Hz，3H，
CH 3-H).IR(KBr)v
maxcm
-1：1754(β-lactam C＝O)，1736(OC＝O).FAB-MS：m/z390(M+H
+)。
Embodiment 44 (5R, 6S)-2-(o-toluic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 74
58 to be raw material, operation is with 47.Get white solid, yield 82%.
1H NMR(D
2O)：δ7.91(d，J＝4.8Hz，2H，Ph)，7.45(m，1H，Ph)，7.29(m，2H，Ph)，5.78(d，J＝8.7Hz，1H，
CHOCO)，5.62(s，1H，H5)，5.39(d，J＝8.7Hz，1H，
CHOCO)，4.11(m，1H，CHOSi)，3.68(d，J＝4.2，1H，H6)，1.30(d，J＝3.6Hz，3H，
CH 3-H).
13CNMR(D
2O)δ：175.16(COONa)，168.20(C＝O)，166.46(C＝O)，142.32(C＝C)，141.41(C＝C)，133.41，132.73，131.69，130.31，129.98，126.87(6C，Ph)，71.99(C6)，66.40(
CHOH)，63.89(C
5)，61.38(CH
2O)，21.84(CH
3CHO)，21.69(PhCH
3)；FAB-MS：m/z 386(M+H
+)，408(M+Na
+)。
Embodiment 45 (5R, 6S)-2-(paracyanobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 75
59 to be raw material, operation is with 47.Get light yellow solid, yield 48%.
m.p.130-131℃.
1H NMR(D
2O)：δ7.83(d，J＝8.4Hz，2H，Ph)，7.52(d，J＝8.7Hz，2H，Ph)，5.70(d，J＝14.7Hz，1H，
CHOCO)，5.55(d，J＝1.2H，1H，H5)，5.35(d，J＝14.7Hz，1H，
CHOCO)，4.03(m，1H，CHOSi)，3.67(dd，J＝1.2，6.9Hz，1H，H6)，1.21(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/Z 397(M+H
+)。
Embodiment 46 (5R, 6S)-2-(p-nitrobenzoic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 76
60 to be raw material, operation is with 47.Get faint yellow solid, yield 74%.
1H NMR(D
2O)：δ8.08(m，2H，Ph)，7.80(d，J＝8Hz，2H，Ph)，5.72(d，J＝14.5Hz，1H，
CHOCO)，5.56(s，1H，H5)，5.38(d，J＝14.5Hz，1H，
CHOCO)，4.03(m，1H，
CHOSi)，3.70(d，J＝6.5Hz，1H，H6)，1.21(d，J＝6.5Hz，3H，
CH 3-H).FAB-MS：m/z 417(M+H
+)，439(M+Na
+)。
Embodiment 47 (5R, 6S)-2-(o-Carboxynitrobenzene) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 77
61 to be raw material, operation is with 47.Get white solid, yield 65%.
1H NMR(D
2O)：δ8.00-7.66(m，4H，Ph)，5.80(d，1H，H5)，5.65and 5.42(m，2H，
CH 2OCO)，4.12(m，1H，CHOSi)，3.80(d，J＝3.9Hz，1H，H6)，1.30(d，J＝3.9Hz，3H，
CH 3-CH).FAB-MS：m/z417(M+H
+)。
Embodiment 48 (5R, 6S)-2-(phenylformic acid) methyl esters-6-[(1R)-the 1-hydroxyethyl]-penem-3-carboxylic acid list sodium salt 78
With 62 adjacent chlorine is raw material, and operation is with 47.Get white solid, yield 55%.
1H NMR(D
2O)：δ7.83(d，J＝8.4Hz，2H，Ph)，7.52(d，J＝8.7Hz，2H，Ph)，5.70(d，J＝14.7Hz，1H，
CHOCO)，5.55(d，J＝1.2H，1H，H5)，5.35(d，J＝14.7Hz，1H，
CHOCO)，4.03(m，1H，CHOSi)，3.67(dd，J＝1.2，6.9Hz，1H，H6)，1.21(d，J＝6.3Hz，3H，
CH 3-H).FAB-MS：m/z 406(M+H
+)。
Claims (12)
1. 2-benzene carboxylic acid ester penem compound is characterized in that, this compound structure is shown in general formula I:
Wherein, n is 0,1 or 2,
The R representative is connected one or more substituting groups on the phenyl ring, is selected from alkoxyl group, the NO of halogen atom, C1-C3
2, CN or C1-C3 alkyl,
R
1Be the basic metal or the ester residue of hydrolysis in vivo.
2. the described 2-benzene carboxylic acid of claim 1 ester penem compound, wherein, the R substituted radical be between position or para-orientation.
3. the described 2-benzene carboxylic acid of claim 3 ester penem compound, wherein, the R substituted radical be between the position replace.
4. claim 1 or 2 or 3 described 2-benzene carboxylic acid ester penem compounds, wherein, R is nitro, CN or halogen atom.
5. the described 2-benzene carboxylic acid of claim 1 ester penem compound, it is a 2-methyl benzoate compounds.
6. the preparation method of the described formula I compound of claim 1, it comprises makes the compound and selected benzene carboxylic acid compound generation esterification with general formula I I, and the process that removes protecting group,
T in the formula
1Be hydroxyl protecting group, T
2Be carboxyl-protecting group.
7. the described preparation method of claim 6 wherein, makes esterification products remove protecting group T in proper order
1And T
2
8. claim 6 or 7 each described preparation methods, wherein, T
1Be trialkyl silica class protecting group, T
2For allyl-based protection or to the nitrobenzyl protecting group.
9. the application of each described 2-benzene carboxylic acid ester penem compound of claim 1-5 in the preparation antibiotics.
10. the described application of claim 9, wherein said 2-benzene carboxylic acid ester penem compound be used to prepare can anti-MRSA antibiotic medicine.
11. being used for preparation, the described application of claim 9, wherein said 2-benzene carboxylic acid ester penem compound can resist responsive golden Portugal bacterium or enterococcal antibiotic medicine.
12. antibacterial combination, the pharmaceutically acceptable acid, salt or the ester that wherein contain arbitrary compound of claim 1-5 are as activeconstituents.
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| CNB2004100003843A CN100417654C (en) | 2004-01-09 | 2004-01-09 | 2-benzene carboxylate penicillen compounds and its preparation method and application |
| HK05105065.4A HK1072425A1 (en) | 2004-01-09 | 2005-06-17 | 2-benzene carboxylate penicillen compounds and its preparation method and application |
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| CN106279178B (en) * | 2016-07-18 | 2019-01-18 | 华东理工大学 | The fluorescence probe and synthetic method of Carbapenem-resistant class antibiotic germ and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4558042A (en) * | 1981-05-06 | 1985-12-10 | Farmitalia Carlo Erba S.P.A. | β-Lactam-containing antibacterial agents and β-lactamase inhibitors |
| US4631150A (en) * | 1983-08-11 | 1986-12-23 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of penems |
| US4849419A (en) * | 1984-09-10 | 1989-07-18 | Hoechst Uk Limited | 7-oxo-4-thia-azabicyclo[3,2,0]hept-2-ene derivatives |
| US4886793A (en) * | 1986-03-06 | 1989-12-12 | Farmitalia Carlo Erba, S.R.L. | Penem derivatives |
-
2004
- 2004-01-09 CN CNB2004100003843A patent/CN100417654C/en not_active Expired - Fee Related
-
2005
- 2005-06-17 HK HK05105065.4A patent/HK1072425A1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4558042A (en) * | 1981-05-06 | 1985-12-10 | Farmitalia Carlo Erba S.P.A. | β-Lactam-containing antibacterial agents and β-lactamase inhibitors |
| US4631150A (en) * | 1983-08-11 | 1986-12-23 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of penems |
| US4849419A (en) * | 1984-09-10 | 1989-07-18 | Hoechst Uk Limited | 7-oxo-4-thia-azabicyclo[3,2,0]hept-2-ene derivatives |
| US4886793A (en) * | 1986-03-06 | 1989-12-12 | Farmitalia Carlo Erba, S.R.L. | Penem derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Activity of New Penems Against Defined MRSA Strain. Daniela Jabes, 等.Bioorganic ＆ Medicinal Chemistry Letters,Vol.3 No.11. 1993 * |
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