CN1887886A - Prepn of carbapenum type antibiotic Faropenum sodium - Google Patents
Prepn of carbapenum type antibiotic Faropenum sodium Download PDFInfo
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- CN1887886A CN1887886A CN 200510027246 CN200510027246A CN1887886A CN 1887886 A CN1887886 A CN 1887886A CN 200510027246 CN200510027246 CN 200510027246 CN 200510027246 A CN200510027246 A CN 200510027246A CN 1887886 A CN1887886 A CN 1887886A
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Abstract
The present invention provides Faropenum sodium preparing process, and the preparation process has short reaction path, no use of strong stimulating substance sulfhydryl compound and chlorosulfoxide, mild reaction condition, no need of purifying intermediate product and simple operation and is suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry technical field.Be specifically related to the preparation method of carbapenum type antibiotic Faropenum sodium.
Background technology
Carbapenem is one group of novel β-Nei Xiananleikangshengsu, structure is different from traditional beta-lactam series products such as penicillin and penems, its parent nucleus and other penam, penem difference are to have replaced sulphur by carbon on 5 yuan of rings, and have the two keys of a C=C between the prosposition.Its 6 hydroxyethyl side chains are transoid conformation in addition.Studies have shown that the special group of this configuration makes this compounds have the stability of height to β-Nei Xiananmei just.Significantly different with the cisoid conformation of common penem.Such microbiotic has the characteristics of has a broad antifungal spectrum, to G
+And G
-Bacterium, aerophil, anerobe all have very strong anti-microbial activity, and stable to the beta-lactam bacterium.
Faropenem is connected to a tetrahydrofuran (THF) group on the 2-position of penem parent nucleus, chemical structure is more stable.It demonstrates broad-spectrum antibacterial activity to aerobic and anaerobic gram positive organism, gram-negative bacteria, particularly the activity to anerobes such as gram positive organisms such as drug-fast staphylococcus, faecalis and bacterioides all is better than existing Perorally administrable antimicrobial agent, all very stable to various β-Nei Xiananmeis, less generation resistance, but to the activity of Pseudomonas aeruginosa a little less than.
Faropenem is that first is orally active in the world, to the stable penems antibiotics of β-Nei Xiananmei.Its external anti-microbial effect compares research with a lot of microbiotic, as cefteram, Cefixime Micronized, cefaclor, amoxycilline Trihydrate bp etc.It is all stronger than the microbiotic that participates in test to suppress the anerobe effect.Up to the present it is the strongest beta-lactam antibiotics of anaerobe resistant.It is more effective than cefteram, Cefixime Micronized, cefaclor, amoxycilline Trihydrate bp to staphylococcus, streptococcus pneumoniae, suis and a lot of Gram-negative bacteria, and is stronger 5～10 times than third generation cephalosporin.This product is 0.78 μ g/ml to the MIC of clinical isolating all bacterium, and it is more much effective than erythromycin, clarithromycin, Roxithromycin, Ofloxacine USP 23 to Campylobacter; It suppresses Peptostreptococci, clostridium difficile is very effective, MIC
90≤ 1 μ g/ml; To bacteroides fragilis MIC
90≤ 4 μ g/ml.The influence of anti-microbial effect unable to take food thing, this product has germicidal action.Stable to all kinds of β-Nei Xiananmeis, also very stable to kidney peptase (DHP-1).
Existingly about preparing Faropenem sodium be: with optically active substance (3R; 4R)-3-(R)-1-tert-butyl dimethyl silica ethyl-4-acetoxyl group nitrogen heterocyclic din-2-ketone is a starting raw material; generate thioesters with (R)-tetrahydrofuran (THF)-2-thiocarboxylic acid generation acyl substituted reaction; be converted into 5 with the ordinary method thioesters then; intramolecularly Witting cyclization obtains penem 6, and deprotection obtains the finished product again.
But the aforesaid method reaction yield is lower, total recovery only 12.5%.Side chain 3 is a sulfhydryl compound simultaneously, and smell is extremely smelly, and preparation is complicated, needs constantly to feed toxic gas hydrogen sulfide and obtains, and human body and environment are had certain harm.In addition, use triphenylphosphine to carry out intramolecularly Witting cyclisation in the reaction process, reaction obtains the difficult separation of penem major-minor product, and yield is lower, is unfavorable for suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and it is low to design a kind of cost, preparation method easy and simple to handle.
The invention provides a kind of method of preparation method faropenem.This method is with optically active substance (3R; 4R)-3-(R)-1-tert-butyl dimethyl silica ethyl-4-acetoxyl group nitrogen heterocyclic din-2-ketone is a starting raw material; under alkaline condition, carry out the azetidinone iii that the acyl substituted reaction obtains the sulfo-trityl as protecting group with three beneze methane thiols; in the presence of diisopropyl ethyl amine with allyloxy oxalyl chloride generation condensation reaction; obtain oxamide iv; not purified; be converted into argent sulfide v; v not purified directly with (R)-tetrahydrofuran (THF)-2-formyl chloride generation replacement(metathesis)reaction obtains vi; vi induces with three ethoxy phosphorus and carries out cyclization and obtain vii; vii sloughs protecting group silicon ether alkane in the presence of tetrabutylammonium fluoride, at four (triphenyl phosphorus) palladium; slough allyl group under triphenyl phosphorus and 2 ethyl hexanoic acid sodium exist and obtain Faropenem sodium.
In this reaction process, the reaction of intermediate VII-VIII is carried out in two steps: at first intermediate VII generates excessive product VII-1 in the presence of three ethoxy phosphorus, make VII-1 self cyclization under anhydrous condition, generate intermediate VIII, and select three ethoxy phosphorus as inducing reagent according to the real reaction yield, avoided the strong stimulation material, respectively go on foot simultaneously the reaction conditions gentleness, intermediate product need not separation and purification can be directly used in the next step, and can carry out waterless operation, method is easy, is fit to industrialization production.
The Faropenem sodium that makes with method of the present invention meets the product set quota, as follows the row analytical results through physico-chemical analysis:
(1) ultimate analysis
1, instrument model: CARLO-ERBA 1106 elemental analysers
2, test result:
Table 1, ultimate analysis data list
| Analysis project | Measured value (%) | Theoretical value (%) |
| C | 40.72 40.85 | 40.90 |
| H | 5.43 5.41 | 5.43 |
| N | 4.03 4.02 | 3.98 |
| S | 8.88 9.04 | 9.08 |
The determination of elemental analysis value of sample is consistent with the molecular formula theoretical value.
(2) UV spectrum
1, instrument model: HP-8452A ultraviolet-visible pectrophotometer
2, instrumental correction: holmium glass
3, test condition: H
2O 0.1mol/L HCl 0.1mol/L NaOH
Sample concentration (μ g/ml) 36.06 32.05 34.05
4, test result:
Table 2, ultraviolet spectrum data tabulation
| Solvent | λmax(nm) | ε(×10 4) | E | Ownership |
| H 2O | 306 | 0.64 | 183.0 | Two keys |
| 0.1mol/L HCl | 320 | 0.77 | 218.2 | Two keys |
| 0.1mol/L NaOH | 218 | 0.61 | 174.3 | Two keys |
5, resolve: the sample UV spectrum mainly be absorbed as π → π
*Transition belongs to the K band for two keys.
(3) infrared spectra
1, instrument model: Nicolet FTIR-670 infrared spectrometer
2, instrumental correction: polystyrene film
3, test condition: KBr pressed disc method
4, test result:
Table 3, ir data tabulation
| Absorption peak cm -1 | Oscillatory type | Group | Intensity |
5, resolve
A, 3000-3500cm
-1Absorption for hydroxyl stretching vibration and water.
B, 2974,2859,1311cm
-1Be saturated hydrocarbon stretching vibration and flexural vibration.
C, 1754cm
-1Carbonylic stretching vibration for beta-lactam.
D, 1650cm
-1Skeletal vibration for two keys.
E, 1578,1382cm
-1Wide strong peak be the asymmetric and symmetrical stretching vibration of carboxylate salt.
F, 1058cm
-1Be the stretching vibration of carbon oxygen singly-bound.
The infrared spectra of g, sample has proved the existence of groups such as carboxylate salt, beta-lactam, methyl, methylene radical, hydroxyl and water
(4) nuclear magnetic resonance spectrum
1, instrument model: Varian INOVA-400 nuclear magnetic resonance analyser
2, test condition: solvent D
2O
1H,
13C, DEPT, COSY, HMQC, HMBC spectrum
3, test result:
Table 4, nucleus magnetic resonance
1H, COSY compose data list
| Sequence number | δ H | Proton number | Multiplicity (J/Hz) | COSY (position) |
| 9 | 1.37 | 3 | d 6.4 | 8 |
| 12 | 1.972.44 | 2 | m | 13 |
| 13 | 2.07 2.11 | 2 | m | 12 |
| 14 | 3.90 4.01 | 2 | q | 13 |
| 6 | 3.93 | 1 | dd | 5 |
| 8 | 4.29 | 1 | quintet 6.4 | 9 |
| 11 | 5.59 | 1 | t 6.8 | 12 |
| 5 | 5.66 | 1 | d 0.4 | 6 |
4, resolve
A methyl is arranged, with the coupling of adjacent methyne, doublet in a, the structure.
Three methylene radical are arranged in b, the structure, and all being shown as non-equivalence is that each methylene radical has two chemical displacement values.So 14 adjacent oxygen of methylene radical are the low field of its chemical displacement value.
Four methynes are arranged in c, the structure.5 protons of beta-lactam and 6 proton couplings, two
Heavy peak; 6 protons also with 8 proton coupling dd peaks; 8 protons show quintet;
11 protons show triplet.
D, since this compound only in water solubleness better, so be solvent with heavy water, reactive hydrogen does not observe.
E, proton nmr spectra have provided the information of methyl, methylene radical, methyne.
Table 5, nucleus magnetic resonance
13C, DEPT, HMQC compose data list
| Sequence number | δ C | Carbonatoms | DEPT | HMQC δ H δ C | HMBC (position) |
| 9 | 15.02 | 1 | ↑ | 1.37-15.02 | |
| 13 | 20.59 | 1 | ↓ | 2.07 2.11-20.59 | |
| 12 | 28.08 | 1 | ↓ | 1.97 2.44-28.08 | |
| 5 | 57.00 | 1 | ↑ | 5.66-57.00 | |
| 8 | 59.66 | 1 | ↑ | 4.29-59.66 | |
| 6 | 63.50 | 1 | ↑ | 3.93-63.50 | |
| 14 | 69.47 | 1 | ↓ | 3.90 4.01-69.47 | |
| 11 | 69.67 | 1 | ↑ | 5.59-69.67 | |
| 2 | 119.92 | 1 | 11 14 | ||
| 3 | 147.51 | 1 | 12 | ||
| 10 | 161.00 | 1 | |||
| 7 | 170.74 | 1 | 5 6 8 |
5, resolve
A methyl is arranged in a, the structure, DEPT spectrum shows ↑, what compose High-Field entirely is 9 methyl carbon, the HMQC spectrum is shown corresponding with its proton.
Three methylene radical are arranged in b, the structure, DEPT spectrum shows ↓.The HMQC spectrum shows that it is the equal non-equivalence of proton of three methylene radical that there is chemical displacement value separately in six protons of three carbon correspondences, low slightly of the mesomethylene carbon chemical shift of 14 adjacent oxygen.
Four methynes are arranged in c, the structure, DEPT spectrum shows ↑, the HMQC spectrum shows corresponding with their proton.
Four quaternary carbons are arranged in d, the structure.1. carbonyl carbon (2): be positioned at minimum of full spectrum, shown in the HMBC spectrum that 7 carbon are correlated with 5,6,8 protons; 10 carbon are not seen reference point.3. two key quaternary carbons (2): 2 and 3 carbon has shown relevant with relevant and 12 protons of 11,14 protons on the HMBC spectrum; 3 direct adjacent nitrogen of carbon are so its chemical displacement value is more a little than low of 2 carbon.
The existence of e, carbon spectrum explanation methyl, methylene radical, methyne, two key and carbonyl etc., the type of its carbon conforms to this chemical structure.
(5) mass spectrum
1, instrument model: Q-Tof micro mass spectrograph
2, test condition: ESI source
3, test result:
4, resolve: this Compound C
12H
14NNaO
5The molecular weight of S is 307 (M).Quasi-molecular ion peak m/z308[M+H]
+Conform to its molecular weight.The ownership of other quasi-molecular ions: m/z330[M+Na]
+M/z637[2M+Na]
+Quasi-molecular ions ownership in the collection of illustrative plates rationally meets the ESI rule.
(6) heat is analyzed
1, instrument model: PE DSC-7 differential scanning calorimeter PE TG-7 thermogravimetric instrument
2, test condition:
3, test result
4, resolve: the DSC collection of illustrative plates is presented at an endotherm(ic)peak between 80-120 ℃; One exothermic peak is arranged between 150-180 ℃, and the Onset value is 163.49 ℃.The weight loss that the TG spectrum shows between 100 ℃-170 ℃ is 12.93%, and the theoretical content of 2.5 parts of water of this compound is 12.78%, the two basically identical.
(7) powder x-ray diffraction analysis
1, instrument model: Philips Analytical X-Ray B.V.
2, test condition: Target:Cu 40kv 20mA scanspeed 0.2
3, test result:
Table 7, the tabulation of X-diffraction data
| D-value | 2Theta | I/I. |
| 16.23 | 5.43 | 100 |
| 8.86 | 9.96 | 20.7 |
| 8.09 | 10.91 | 29.0 |
| 4.67 | 18.98 | 43.2 |
| 3.26 | 27.25 | 20.3 |
The X-ray diffracting spectrum of sample has provided several a tree names of angle, interplanar distance and relative intensity.
(8) integration analysis
1, the determination of elemental analysis value of sample is consistent with this compound molecule formula theoretical value.
2, in the structure
Feature performance: the absorption peak of signify hydroxy, carbonyl and methyl in the IR spectrum.
1The HNMR spectrum shows methyl and is 5,6 protons of doublet, beta-lactam.
13The low territory, place of CNMR spectrum has shown amidocarbonylation carbon, two key quaternary carbon, methine carbon, methyl carbon.This segmental existence of these information supports.
3, in the structure
Feature performance: the IR spectrum has shown the absorption peak of ehter bond.
1The HNMR spectrum has shown the non-equivalence of methene proton on the furan nucleus.
13CNMR (DEPT) spectrum has shown and the corresponding carbon of these protons.This segmental existence of these information supports.
4, in the structure
Feature performance: the IR spectrum shows COO
-Symmetry and asymmetric absorption peak.
13The CNMR spectrum shows carbonyl carbon.
5,2.5H in the structure
2The feature of O: IR spectrum is presented at the absorption broad peak of water between about 3000-3500 wave number.The TG spectrum has shown the weightlessness of 2.5 parts of water.
6, the proton number of proton nmr spectra, the carbonatoms of carbon spectrum, the type of DEPT spectrum carbon all conforms to this compound.
7, mass spectral accurate quasi-molecular ions, molecular weight adds the sodium peak, conforms to the molecular weight of this compound.
8, in sum, the chemical structure of sample can be proved conclusively and be Faropenem sodium.
By the Faropenem sodium that the inventive method makes, proved conclusively through physico-chemical analysis.
Embodiment
Embodiment 1, the preparation (3S, 4R)-3-[(R)-the 1-tert-butyl dimethyl silica ethyl]-4-three benzylthios-nitrogen heterocyclic din-2-ketone (III)
7.65g sodium hydrogen is dissolved among the 164ml DMF, be added drop-wise to 52.77g triphenyl mercaptan (294.35)/287ml DMF solution in 0 ℃, dropwised in 0.5 hour, mixture stirred after 10 minutes, added 50g 4AA/164ml DMF solution in 15 minutes, keep 0 ℃, continue to stir 45 minutes, reaction mixture in the frozen water solution of going into the 900g saturated ammonium chloride, is used 1000ml extracted with diethyl ether (three times), ether layer washes with water twice, the saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, evaporate to dryness, solid residue 300ml ether washed twice, drain, drying is weighed, get the 72g solid, yield 82.2%.Fusing point: 94-96 ℃
TLC: sherwood oil: ethyl acetate=4: 1 Rf=0.3
Embodiment 2, the preparation (3S, 4R)-1-(allyl oxygen oxalyl group)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4 three benzylthios-nitrogen heterocyclic din-2-ketone (IV)
In the there-necked flask of 1000ml, add the dissolving of 50g " III " and 50ml methylene dichloride, in bathing, cryosel is cooled to-10 ℃, drip methylene dichloride (40ml) solution of single oxalyl chloride allyl ester 25g, drip methylene dichloride (40ml) solution of triethylamine 18g again, keep dropping temperature to be no more than-5 ℃, mixture is in-5 ℃--and 10 ℃ were reacted 1.5 hours, added water (150ml) dilution, extracted with methylene dichloride (100ml), merge organic phase, wash saturated solution of sodium bicarbonate washing, anhydrous sodium sulfate drying with water, revolve steam faint yellow solid 58g, yield 95%.
TLC: sherwood oil: ethyl acetate=4: 1 Rf=0.4
Embodiment 3, the preparation (3S, 4R)-1-(allyl oxygen oxalyl group)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-sulphur money base-nitrogen heterocyclic din-2-ketone (V)
To go up step product " IV " and be dissolved in the 1000ml methyl alcohol, add methyl alcohol (500ml) solution of pyridine 2ml (25mmol) and Silver Nitrate (100g).Mixture 10 ℃ of following lucifuges again stirred 3 hours, concentrated, and methylene dichloride (1000ml) extracts.Organic layer water (800ml) is washed, anhydrous magnesium sulfate drying, and evaporate to dryness gets silver salt.Need not purifying, be directly used in the next step.
Embodiment 4, the preparation (3S, 4R)-1-(allyl oxygen oxalyl group)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-[(2R)-the tetrahydrofuran base sulfenyl] nitrogen heterocyclic din-2-ketone (VII)
R-tetrahydrofuran (THF)-2-formic acid 31.9g at room temperature mixes with the 60ml sulfur oxychloride, be stirred to no bubble and emerge, reflux is after 15 hours, with the solution decompression evaporate to dryness, add the dissolving of 350ml methylene dichloride, under 0 ℃, be added dropwise in the 700ml dichloromethane solution of product V.Finish, lucifuge stirred 15 minutes, had grey black look solid to produce.Suction filtration, filtrate is with saturated sodium bicarbonate aqueous solution (500ml) washing, and water (500ml) is washed, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets yellow oil, can directly cast single step reaction.TLC: sherwood oil: ethyl acetate=2: 1 Rf=0.4.
Embodiment 5, the preparation (5R, 6S)-6-[(1R)-the 1-tert-butyl dimethyl silica ethyl]-2-[(2R)-tetrahydrochysene-2-furans] penem-3-allyl carboxylate (VIII)
Crude product " VII " at room temperature mixes with 47g three ethoxy phosphorus, be warming up to 70 ℃ and stirred 1 hour, decompression steams unnecessary three ethoxy phosphorus, and reaction mixture refluxed 3 hours in the dimethylbenzene of 200ml, to going in the 100ml water, ethyl acetate (600ml) extraction merges organic layer, anhydrous sodium sulfate drying, steam solvent, fast post (100-200 order silica gel 2000g) chromatogram (ethyl acetate: purifying sherwood oil=1: 4), white solid " VIII " 31g, mp=70～72 ℃.Yield 55～60%.
TLC: sherwood oil: ethyl acetate=5: 1 Rf=0.7
Embodiment 6, the preparation (5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-[(2R)-tetrahydrofuran (THF)-2-yl] penem-3-allyl carboxylate (IX)
90g " VIII " is dissolved among the 1000ml THF, the THF (174g/500ml) that adds tetrabutyl ammonium fluoride under the room temperature respectively, stirred 72 hours under the room temperature, TLC detects to the disappearance of raw material point, and question response finishes, and steams THF, ethyl acetate (1000ml) dilution, sodium bicarbonate water (500ml * 4) solution washing, drying, evaporate to dryness gets target compound " IX " 45g.
TLC: sherwood oil: ethyl acetate=3: 1 Rf=0.4
Embodiment 7, preparation (5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran (THF)-2-yl]-4-thia-1-azabicyclo [3.2.0] hept-2-ene"-2-sodium formiate two sesquialter hydrates
" IX " 41g is dissolved in the 370ml methylene dichloride, adds triphenyl phosphorus 1.64g and four (triphenyl phosphorus) palladium 1.5g respectively, the ethyl acetate of Sodium isooctanoate 20g (230ml) solution, stirring at room 3.5 hours, TLC detects raw material point and disappears, and adds 150ml water, stir layering, water layer washs with ethyl acetate (100ml * 3), and temperature control is below 50 ℃, remove water under reduced pressure, resistates adds acetone (200ml), stirs, there is solid to separate out, suction filtration, washing with acetone, reduced pressure at room temperature gets crude product.
Claims (4)
1, a kind of preparing Faropenem sodium, it is characterized in that this method comprises the following steps: that (1) is with optically active substance (3R, 4R)-3-(R)-1-tert-butyl dimethyl silica ethyl-4-ethanoyl oxygen base nitrogen heterocyclic din-2-ketone is a starting raw material, carries out the azetidinone iii that the acyl substituted reaction obtains vulcanizing trityl as protecting group with three beneze methane thiols under alkaline condition; (2) compound i ii and allyloxy oxalyl chloride generation condensation reaction in the presence of diisopropyl ethyl amine obtains oxamide iv; (3) compound i v is not purified, is converted into argent sulfide v; (4) compound v not purified directly with (R)-tetrahydrofuran (THF)-2-formyl chloride generation replacement(metathesis)reaction obtains vi; (5) compound vi induces with three ethoxy phosphorus and carries out cyclization and obtain vii; (6) compound vii sloughs protecting group silicon ether alkane in the presence of tetrabutylammonium fluoride, sloughs allyl group and obtain Faropenem sodium in the presence of four triphen phosphorus palladiums, triphenyl phosphorus and 2 ethyl hexanoic acid sodium.
2, a kind of preparing Faropenem sodium according to claim 1 is characterized in that wherein the temperature of reaction of step (1) is 0 ℃, and alkaline condition is pH=8-10, adopts weak base to be: ammonium sulfate or ammonium chloride.
3, a kind of preparing Faropenem sodium according to claim 1, it is characterized in that the reaction of wherein said step (2), in reactor, put into compound i ii and solvent earlier, then under-5--10 ℃ condition, drip the dichloromethane solution of single oxalyl chloride allyl ester earlier, dripping the dichloromethane solution of triethylamine again, temperature of reaction is-5--10 ℃.
4, a kind preparing Faropenem sodium according to claim 1 is characterized in that wherein said step (6) comprises the following steps: from compound vii preparation method faropenem
(1) preparation compound viii:
Compound vii mixes with three ethoxy phosphorus, being warming up to 70 ℃ stirred 1 hour, unnecessary three ethoxy phosphorus are removed in decompression, reactant refluxed in dimethylbenzene 3 hours, and reaction is finished, and reactant is poured in the water, ethyl acetate extraction, merge organic layer, drying, desolventize, behind column chromatography and chromatogram purification, get compound viii;
(2) preparation compound i x
Compound viii is dissolved in THF, adds the THF solution of tetrabutyl ammonium fluoride, and stirring at room 72 hours is controlled reaction with TCL and finished, and removes THF, the ethyl acetate dilution, and sodium bicarbonate aqueous solution washing, drying, evaporate to dryness get compound i x;
(3) preparation method faropenem 2.5 hydrates
Compound i x is dissolved in methylene dichloride, adds the ethyl acetate solution of triphenyl phosphorus, four (triphenyl phosphorus) palladium and Sodium isooctanoate, stirring at room 3.5 hours, TCL control reaction finishes, and adds water, layering, water layer washs three times with ethyl acetate, remove water under reduced pressure under 50 ℃ of temperature, resistates adds acetone, stirs, separate out solid, filter, the filter cake washing with acetone gets Faropenem sodium 2.5 hydrates after the drying at room temperature.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235044B (en) * | 2008-03-03 | 2010-11-03 | 南京华威医药科技开发有限公司 | Method for preparing faropenem daloxate |
| CN104165957A (en) * | 2014-08-15 | 2014-11-26 | 珠海联邦制药股份有限公司 | Method for determining content of bipolymer impurities in faropenem sodium |
| CN107337684A (en) * | 2017-08-10 | 2017-11-10 | 沈阳三九药业有限公司 | A kind of preparation method of Faropenem sodium |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2354558A1 (en) * | 1999-10-12 | 2001-04-19 | Suntory Limited | Oral pharmaceutical composition |
| GB0116076D0 (en) * | 2001-06-02 | 2001-08-22 | Astrazeneca Ab | Methods |
| US20030236265A1 (en) * | 2002-05-23 | 2003-12-25 | Sayada Chalom B. | Methods of treating bacterial infections and diseases associated therewith |
| ES2339003T3 (en) * | 2002-08-29 | 2010-05-14 | Activbiotics Pharma Llc | RIFALAZIL TO TREAT INFECTIONS BY CLOSTRIDIUM DIFFICILE. |
| WO2004089378A1 (en) * | 2003-04-04 | 2004-10-21 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine derivative |
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2005
- 2005-06-29 CN CNB2005100272469A patent/CN100398546C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235044B (en) * | 2008-03-03 | 2010-11-03 | 南京华威医药科技开发有限公司 | Method for preparing faropenem daloxate |
| CN104165957A (en) * | 2014-08-15 | 2014-11-26 | 珠海联邦制药股份有限公司 | Method for determining content of bipolymer impurities in faropenem sodium |
| CN104165957B (en) * | 2014-08-15 | 2016-02-17 | 珠海联邦制药股份有限公司 | The assay method of dimer impurity content in a kind of faropenem sodium raw materials |
| CN107337684A (en) * | 2017-08-10 | 2017-11-10 | 沈阳三九药业有限公司 | A kind of preparation method of Faropenem sodium |
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