CN102475704B - Preparation method of stable prulifloxacin mesylate - Google Patents
Preparation method of stable prulifloxacin mesylate Download PDFInfo
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Abstract
Prulifloxacin has low bioavailability due to poor water solubility. The invention relates to a novel prulifloxacin mesylate and a preparation thereof, a kit comprising an antibiotic preparation of the novel prulifloxacin mesylate, and application of the novel prulifloxacin mesylate in preparing an anti-bacterial infection medicine. Specifically, the invention particularly relates to a novel preparation for injection of a medicine, with a chemical name of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxole-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-mesylate, which can be stably stored. Prulifloxacin is directly injected for administration in the form of thiabutyldine quinoline mesylate, so that the solubility, bioavailability and curative effect of prulifloxacin are improved.
Description
Technical field:
The present invention relates to new prulifloxacin mesylate and preparation thereof, comprise test kit and the application of this new prulifloxacin mesylate in a kind of bacterial-infection resisting medicine of preparation of the plain preparation of this medicinal antibiosis.Specifically, being particularly related to the chemical name that a kind of new injection can stablize storage is: 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1, the 3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the also pharmaceutical preparation of [3,2-a] quinoline-3-mesylate of sulfur nitrogen heterocycle butane.
Background technology:
Infected by microbes is the principal element that threatens human health, the mankind have found multiple antibacterials in the process of disease struggle: beta-lactam, Macrolide, aminoglycoside, other antibioticses and synthetic drug class, in synthetic drug, comprise maximum class antibacterials: quinolones, wherein ciprofloxacin, ofloxacin, levofloxacin, pefloxacin etc. have been widely used in clinically, have become an important clinically class antimicrobial drug.Yet, these antimicrobial drugs can not satisfy increasing in recent years and for refractory disease be the treatment that chronic green pus bacterium infects disease and gram positive bacterial infection disease, and along with the extensive use of antibacterials, the generation of bacterial drug resistance has become the difficult problem in the clinical treatment.Therefore, people still synthesize the antibiotic medicine that bacteriostatic activity is higher, antimicrobial spectrum is wider constantly, and provide more dosage form to satisfy clinical needs.
Summary of the invention:
The object of the invention just is based on this thinking, has designed and studied that a kind of bacteriostatic activity is higher, has a broad antifungal spectrum and the high novel class prulifloxacin mesylate antibiotic medicine of bioavailability.
Prulifloxacin (prulifloxacin) is third generation fluoroquinolones broad spectrum antibiotic, researches and develops success jointly by Japanese new drug company and Meiji Seika Kaisba company, gets permission to go on the market in Japan in July, 2002.This medical instrument has good antibacterial activity in vitro, gram positive bacteria and gram-negative bacteria there is broad-spectrum antibacterial action, strong to golden Portugal bacterium, Haemophilus influenzae, Klebsiella Pneumoniae, shigella dysenteriae and salmonella antibacterial activity, particularly Pseudomonas aeruginosa there is good antibacterial activity; This product tissue permeability is good, widely distributed, and the concentration in the tissue is the several times of blood concentration.
This medicine is suitable with ciprofloxacin, ofloxacin, levofloxacin and Sparfloxacin to the activity of most gram positive bacterias, and the activity of gram negative bacteria is better than ciprofloxacin, ofloxacin or quite.This medicine has good bactericidal action, to staphylococcus aureus, colon bacillus, serratia marcescens, Pseudomonas aeruginosa, even in the following short time of 1/2MIC, namely be bactericidal action, be better than ofloxacin and ciprofloxacin particularly to the antimicrbial power of the gram negative bacteria headed by the bacillus pyocyaneus considerably beyond other xacin-series, also surpass other antibiolicss of listing at present.
The present invention is to be base substance with the prulifloxacin, improves dissolubility behind the one-tenth mesylate, thereby further improves bioavailability.Its chemical name is: 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-mesylate (prulifloxacin mesylate) also.
Prulifloxacin mesylate with antibacterial action of the present invention, its structural formula is as follows:
This pharmaceutical composition, by weight, 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1 by 0.1%～99.9%, the 3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the sulfur nitrogen heterocycle butane also form by [3,2-a] quinoline-3-mesylate chemical compound and 0.1%～99.9% medicine acceptable carrier.
The present invention also provides 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1, the 3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] also [3,2-a] quinoline-3-mesylate chemical compound and preparation of drug combination method thereof and with the application of their preparation antibacterials of sulfur nitrogen heterocycle butane.
Preferred pharmaceutical composition of the present invention is the dosage form of the pharmaceutical dosage forms as parenteral, particularly drug administration by injection.Salt of the present invention (prulifloxacin mesylate) and injection thereof can effectively be widely used in field of medicaments.
The invention provides a kind of stablizing and store and the pharmaceutical preparation with powder or aqueous solution preparation form administration that water-soluble mesylate of the present invention (prulifloxacin mesylate) is made, in order to be applied to clinical treatment by the medical domain expert.
Injection of the present invention can be the transfusion injection of injectable powder or aqueous injection or 0.9% sodium chloride, the transfusion injection that perhaps contains the different content glucose solution, for injection, the liquid unit doses of preparation contains aseptic raw material of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.The preparation of solution is normally passed through material dissolution in a kind of carrier, filter-sterilized before it is packed into a kind of suitable bottle or ampoule, sealing then.Adjuvant for example a kind of local anesthetic, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into that this compositions is freezing, and under vacuum, water is removed.
The present invention also comprises the test kit that injectable powder and injection solvent are formed.This test kit includes the solvent that injectable powder of the present invention and a kind of injectable are used, and the solvent that injectable powder and injectable are used is discrete, is packaged in the same packing box.The proportioning of the quantity of solvent that injectable powder and injectable are used is according to the using method configuration, and the injectable powder of every 100mg dosage is equipped with the solvent that 5～500mL injectable is used.Described injectable is selected from solvent: water for injection, sodium chloride for injection infusion solution, glucose for injection infusion solution.
Specifically can be but be not limited to: 100mg or 200mg injectable powder; 5mL or 10mL water; 0.9% sodium chloride injection of 100mL or 250mL or 500mL or 5% glucose injection.
The preparation method of dry powder injection provided by the invention comprises raw materials of compound of the present invention is made the freeze dry sterile powder end through freeze-drying, jumps a queue and makes with aluminium lid sealing.
The preparation method of injection provided by the invention, comprise raw materials of compound of the present invention added injection water dissolving after, transfer pH to 5.0～7.0, decolouring, depyrogenation, behind coarse filtration and fine straining, fill, Sai Sai, roll lid, sterilize, put cold after, namely.
Intravenous drip provided by the invention is with the preparation method of transfusion, comprise raw materials of compound of the present invention and glucose or sodium chloride added the dissolving of injection water after, transfer pH5.0～7.0, decolouring, pyrogen, behind coarse filtration and fine straining, fill, Sai Sai, roll lid, sterilize, put cold after, namely.
Injection of the present invention, chemical compound 50～1000mg of the present invention can be contained in each preparation unit, and all the other can be by the carrier that is subjected to for medicine, and described medicine can be the general carrier of galenic pharmacy by the carrier that is subjected to.Described carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, the methanesulfonic acid cysteine, TGA, methionine, vitamin C, EDTA sodium, the EDTA disodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, methanesulfonic acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Preparation of the present invention is determined usage and dosage according to patient's situation in use.
Following data declaration beneficial effect of the present invention by experiment:
Table 1 prulifloxacin and mesylate dissolubility thereof are relatively
Sample title dissolubility (mg/mL)
Prulifloxacin 2.64
Prulifloxacin mesylate 35.38
Can obviously draw such conclusion from table 1: thiophene fourth pyridine quinoline carboxylic acid (is 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1, the 3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid) water-soluble hardly, behind its one-tenth mesylate (being the methanesulfonic acid prulifloxacin), water solublity increases greatly.
Stability experiment research
An amount of prulifloxacin mesylate is added in the Brown Glass Brown glass bottles and jars only, add 5mL water, dissolve, seal, placed 60 ℃ of drying baker 10 days, use high performance liquid chromatography (HPLC) to carry out analysing impurity content at the 256nm place subsequently.
60 ℃ of stability experiment results of study of table 2
Time (my god) the methanesulfonic acid prulifloxacin
1 0.10
3 0.13
5 0.16
10 0.23
An amount of prulifloxacin mesylate is added in the Brown Glass Brown glass bottles and jars only, add 5mL water, dissolve, seal, place 25 ℃ to place 6 months, use high performance liquid chromatography (HPLC) to carry out analysing impurity content at the 256nm place subsequently.
25 ℃ of stability experiment results of study of table 3
Time (moon) methanesulfonic acid prulifloxacin
0 0.10
3 0.11
6 0.13
Show with two experimental results of room temperature by 60 ℃: the prulifloxacin mesylate has good stable.
It below is the basic experiment of methanesulfonic acid prulifloxacin
(1) soluble test
It is an amount of to get the prulifloxacin mesylate, and porphyrize takes by weighing in right amount, places the test tube that is added with 10mL water, 25 ± 2 ℃ every jolting in 5 minutes 30 seconds, observed the dissolving situation in 30 minutes, as when can't see particles of solute, be dissolving fully.The total amount that the result adds solute is 1.25g.According to the regulation of two ones of Chinese Pharmacopoeia versions in 2010, result of the test shows that this product is easily molten in water.
(2) pH value of solution
Get the about 0.2g of prulifloxacin mesylate, add water 40mL dissolving, measure pH value according to two appendix VI of Chinese Pharmacopoeia version in 2010, the result is 5.1.
(3) abnormal toxicity test of prulifloxacin mesylate
It is an amount of to get the prulifloxacin mesylate, adds 0.9% sodium chloride injection and makes the need testing solution that contains this product 30mg among every 1mL.Qualified for mice health on probation, body weight 17～20g raises by normal raising condition before the test.Get 10 of mices, male and female half and half, behind tail vein injection need testing solution 0.5mL, the normal raising observed the existence situation of mice in 48 hours respectively for every mice.The whole mices of result did not see death in 48 hours, the undue toxicity checks up to specification.It is a 200mg that this product preparation is used for clinical dosage, i.e. 2.86mg/kg (calculating with average weight 70kg); This test dose is greater than more than 200 times of human dosage, the clinical use safety of this product preparation.
The usage and dosage of prulifloxacin mesylate injectable powder: this product (specification 200mg/ bottle) is fully dissolved with water for injection, be mixed with every 1mL and contain the solution of 20mg, join in 0.9% sodium chloride injection or 5% glucose injection of 100mL, the 30-60min angular vein instils fast again.
The usage and dosage of prulifloxacin mesylate injection: get 1 bottle of this product, join in 0.9% sodium chloride injection or 5% glucose injection of 100mL, the 30-60min angular vein instils fast.
Transfusion: get this product, directly instil fast in the 30-60min angular vein.
Dosage: adult's usual amounts is a 200mg.
Chemical compound of the present invention and pharmaceutical preparation thereof, the advantage that has comprises: bacteriostatic activity height, has a broad antifungal spectrum and bioavailability height, this safety of medicine is effective, and is particularly very effective to respiratory system infection and biliary tract infection, infective enteritis; In addition, it infects also effective to urinary tract infection and surgery, department of obstetrics and gynecology, department of dermatologry, ophthalmology, dentistry etc.Mesylate of the present invention, its water solublity are fairly good, thereby are conducive to make injection preparation.This medicine directly injects in the body with activity form, improved bioavailability, and onset is rapid, its clinical efficacy also will strengthen greatly, some can improve by injection by the disease that oral administration can't reach therapeutic effect originally, so this preparation also can enlarge the indication scope of oral formulations.The invention of prulifloxacin mesylate injection will bring glad tidings for vast infectious disease patient, can produce the huge social benefit simultaneously.All not having the prulifloxacin mesylate is applied to clinical bibliographical information with the injection form both at home and abroad at present.
The specific embodiment:
Preparation example 1:6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the also preparation of [3,2-a] quinoline-3-carboxylic acid of sulfur nitrogen heterocycle butane
1) 3, the preparation of 4-two fluoro-dithio formic acid-aniline-triethylamine salt (A):
Under the nitrogen protection; 129g (1.00mol) difluoroaniline is placed the 1L reaction bulb, add 202g (2.00mol) triethylamine again, be cooled to 5 ℃; slowly drip 84g (1.10mol) Carbon bisulfide; finish in 5～10 ℃, stirring reaction spends the night, and filters; ether drip washing filter cake; the room temperature vacuum drying gets faint yellow solid 294.2g, and yield is 96.0%.TLC developing solvent: petroleum ether: ethyl acetate: 4: 1, Rf=0.60
2) 3, the preparation of 4-difluorophenyl isothiocyanate (B):
Under the nitrogen protection, in the 1L reaction bulb, add 306g (1.00mol) self-control A successively, the 450mL dichloromethane; stir, frozen water is cooled to 5 ℃, drips 119g (1.10mol) chloroformate acetate; finish in 5～10 ℃ of reactions 3 hours, in reactant impouring 500g mixture of ice and water, stir evenly; layering; water layer merges organic facies with dichloromethane (200mL * 3) extraction, respectively water and saturated common salt water washing; tell organic layer, add MgSO
4Drying removes by filter desiccant, concentrated filtrate, and 80～82 ℃/5mmHg fraction is collected in distilling under reduced pressure.Get faint yellow aqueous thing 121g, yield is 77.1%.
TLC developing solvent: petroleum ether: ethyl acetate: 6: 1, Rf=0.65
3) preparation of 6,7 two fluoro-4-oxos-2-ethylthio quinoline-3-carboxylic acid second fat (C):
Under nitrogen protection, drip diethyl malonate 128g (0.80mol) in potassium hydroxide 53.4g (0.80mol) dioxane (700mL) to containing, in 35 degree reflections 2 hours; be down to room temperature; in 1 hour, in reactant liquor, drip B and reflected 15 hours that under this temperature filter, solid transfer is to DMF500mL; in about 0～5 ℃, drip 87.2g (0.80mol) bromoethane; react after 2 hours, be warming up to 60 ℃, reacted 5 hours; cold slightly; add 1.5L water and 300mL dichloromethane, water merges organic layer with dichloromethane (300mL * 2); water (200mL * 2) washing; tell organic layer, add the desiccant drying, filter; filtrate decompression concentrate faint yellow oily thing; residue adds the 500mL diphenyl ether, and reaction is 30 minutes in outer temperature oil bath, and diphenyl ether is removed in distilling under reduced pressure; residual liquid adds normal hexane 500mL; cool off 0～5 ℃, separate out a large amount of faint yellow crystallizations, filter; with the normal hexane washing that contains 5% ethanol, vacuum drying gets C 188g yield 75%.mp：127.4～128.1℃。
TLC developing solvent: petroleum ether: ethyl acetate; 5: 1, Rf=0.50
4) preparation of 6,7 two fluoro-4-acetoxyl groups-2-ethylthio quinoline-3-carboxylic acid second fat (D):
100g under nitrogen protection (0.32mol) self-control intermediate C, 400mL triethylamine, the 1L dichloromethane drips acetic anhydride and is cooled to 5 ℃ under the ice-water bath; add 49g (0.48mol), finish and stirred 3 hours, reactant liquor is poured in the frozen water; layering, water merges organic facies with dichloromethane (300ml * 3) extraction; organic layer is told in washing; add the desiccant drying, the filtering desiccant concentrates and steams except dichloromethane; get little yellow crystals powder 102.9g, yield 90.5%.mp：64.1～66.3℃。
TLC developing solvent: petroleum ether: ethyl acetate: 5: 1, Rf=0.58
5) (±) 6,7 two fluoro-1-methyl-4-oxo-4H-[1,3]-the also preparation of [3,2-a] quinoline-3-carboxylic acid second fat (E) of sulfur nitrogen heterocycle butane:
80g (0.22mol) self-control intermediate D, 500mL normal hexane are placed reaction bulb, under reflux state, in 4 hours, drip hexane (100mL) solution of 65g (0.48mol) sulfonic acid chloride, finish and continue to reflux 4 hours, evaporated under reduced pressure gets faint yellow oily thing intermediate E, add 700mL oxolane and 108g (1.32mol) anhydrous sodium acetate, refluxed 4 hours, be cooled to room temperature, pour in the 2L frozen water, separate out crystal, filter, be washed to neutrality, drying gets light brown crystallization 58.2g, yield 85.0%.mp；202.2-204.1℃。
TCL developing solvent: petroleum ether: ethyl acetate: 5: 1, Rf=0.31
6) (±) 6,7 two fluoro-1-methyl-4-oxo-4H-[1,3]-the also preparation of [3,2-a] quinoline-3-carboxylic acid (F) of sulfur nitrogen heterocycle butane:
Under the nitrogen protection; 56g (0.80mol) potassium hydroxide, the 600mL tert-butyl alcohol and 200mL water are joined in the reaction bulb, and stirring and dissolving stirs adding 62.3g (0.2mol) intermediate E down; refluxed 4 hours; add 800mL water, be neutralized to neutrality with the hydrochloric acid of 2mol/L, separate out precipitation; filter; filter cake washes with water, and vacuum drying gets the little yellow crystalline powder of 51g, yield 90.0%.
TCL developing solvent: petroleum ether: ethyl acetate: acetic acid: 3: 1, Rf=0.40
7) 4-(1-piperazine)-methyl-5-methyl isophthalic acid, the preparation of 3-Er Evil cyclopentenes-2-ketone (G):
Under nitrogen protection, with the 4-bromomethyl-5-methyl isophthalic acid of 22.2g (0.10mol) content 87%, 3-Er Evil cyclopentenes-2-ketone is dissolved among the 60mL DMF; room temperature is dripped and is added the DMF solution 40mL of 17.2g (0.20mol) Piperazine anhydrous; finish in room temperature reaction 3 hours, add 200mL water, with dichloromethane (100mL * 3) extraction; merge organic layer; add the desiccant drying, remove by filter desiccant, concentrated filtrate; get 17.5g red solid G, yield 88.8%.
8) 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the also preparation of [3,2-a] quinoline-3-carboxylic acid (prulifloxacin) of sulfur nitrogen heterocycle butane:
Under nitrogen protection, 42.5g (0.15mol) intermediate F, 30g (0.30mol) potassium bicarbonate and 300mLDMF are added in the reaction bulb, stirring at room half an hour; add intermediate G 49.6g (0.25mol) again, stirring reaction 5 hours is in reactant liquor impouring 1L frozen water; with 0.5mol/L adjust pH about 7.0, there are a large amount of precipitations to separate out, filter; water washing; vacuum drying, crude product thermosol in the 1L acetonitrile, heat filtering; slowly crystallisation by cooling gets little yellow crystal g, yield 70%.Mp:219.3～221.2 ℃, purity 99.87% (HPLC normalization method),
1H-NMR (500MHz, DMSO-d
6) δ 2.30 (s, 3H), 2.34 (d, J=7.5Hz, 3H), 2.63 (m, 4H), 2.90 (m, 4H), 3.17 (s, 2H), 6.18 (q, J=7.5Hz, 1H), 6.82 (d, J=7.8Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 14.00 (s, 1H).
TCL developing solvent: chloroform: methanol: ammonia: 1: 1: 0.1, Rf=0.62
Embodiment 1:
A. the preparation of prulifloxacin mesylate
In the 1L three-necked bottle, add prulifloxacin and the 500mL acetonitrile that 10g preparation example 1 makes, after stirring dissolving half an hour that refluxes, continue to stir adding methanesulfonic acid 2.70g down, stirred 30 minutes, add 50mL distilled water and active carbon 1.0g, be warming up to backflow gradually, insulation 2h.Anti-complete substantially, solution becomes must be clarified, filtered while hot, and filtrate is put refrigerator cold-storage and is spent the night, and a large amount of crystal are separated out, sucking filtration, filter cake washing with alcohol twice, each 25mL.The gained solid gets off-white color or light yellow solid 9.74g, yield 83.0% at 40 ℃ of following drying under reduced pressure 10h.
B. the preparation of injection prulifloxacin mesylate
Get prulifloxacin mesylate raw material 50g, place suitable sterile chamber, add sterile water for injection to 1000ml, stirring makes dissolving, adds 0.0596 active carbon of amount of preparation then, stirs 10 minutes, filter with aseptic suction funnel shop sterilization filter paper, use the G6 sintered glass funnel fine straining through sterilization again, filtrate is made 1000 bottles in freezing powder through freeze-drying, jumps a queue and makes with aluminium lid sealing.
C. the preparation of prulifloxacin mesylate injection
Get 200g prulifloxacin mesylate raw material and put dense joining in the cylinder, it is an amount of to add the injection water, fully stirs to make it to dissolve fully: transfer pH to 5.0～7.0 with the 0.1mol/L methanesulfonic acid, add the needle-use activated carbon of dosing amount 0.05% (w/v), backflow 15min; After 0.6 μ m titanium filter stick filtration decarburization, medicinal liquid is sent into rare joining in the cylinder, add water for injection to 1000mL, stir 15min.Sampling survey pH value, content qualified after, behind 0.45um polysulfones filter coarse filtration and 0.22 μ m polysulfones filter fine straining, medicinal liquid is sent into the next procedure fill becomes 1000 bottles, sealing by fusing, after 30 minutes, put cold through 115 ℃ of pressure sterilizings.After the passed examination, packing namely.
D. the preparation of prulifloxacin mesylate transfusion
Get 400g prulifloxacin mesylate raw material, sodium chloride (or glucose) is put dense joining in the cylinder, it is an amount of to add the injection water, fully stir and make it to dissolve fully: transfer pH to 5.0～7.0 with the 0.1mol/L methanesulfonic acid, add the needle-use activated carbon of dosing amount 0.05% (w/v), backflow 15min; After 0.6 μ m titanium filter stick filtration decarburization, medicinal liquid is sent into rare joining in the cylinder, add water for injection to 100000mL, stir 15min.Sampling survey pH value, content qualified after, behind 0.45 μ m polysulfones filter coarse filtration and 0.22 μ m polysulfones filter fine straining, medicinal liquid is sent into the next procedure fill becomes 1000 bottles, Sai Sai, rolls lid, after 30 minutes, put cold through 115 ℃ of pressure sterilizings.After the passed examination, packing namely.
Embodiment 3: the prulifloxacin mesylate of preparation is to the endogenous protective effect of colon bacillus, klebsiella pneumoniae infecting mouse
Be contrast with the prulifloxacin, comparative study the endogenous protective effect of prulifloxacin mesylate to colon bacillus, pneumonia gram clouds uncle bacillus infection mice.This research is subjects with the Kunming mouse, and test strain (colon bacillus, klebsiella pneumoniae) obtains from the hospital clinical separation.Animal is divided into 7 groups, and the dosage that each treated animal gives investigational agent is respectively 3.5,2.45,1.715,1.20,0.84,0.59 and 0.41mg/kg body weight (in prulifloxacin), and the mouse peritoneal injection was used bacterium liquid after 10 minutes, the subcutaneous injection administration.The duration of test mice is raised by normal condition, observes the existence situation in the mice after the administration 48 hours.
The prulifloxacin mesylate is to the endogenous protective experimental result of colon bacillus infecting mouse
Table 1. experimental drug (prulifloxacin mesylate)
Table 2. contrast medicine (prulifloxacin)
Annotate: ED
50Computational methods for adopting the routine processes of bliss method, calculate and get.The data of 0.41mg/kg～3.5mg/kg7 dosage group have been adopted during calculating.
The prulifloxacin mesylate is to the endogenous protective experimental result of klebsiella pneumoniae infecting mouse
Table 3. experimental drug (prulifloxacin mesylate)
Table 4. contrast medicine (prulifloxacin)
Annotate: ED
50Computational methods for adopting the routine processes of bliss method, calculate and get.Juice has adopted the data of 0.41mg/kg～3.5mg/kg7 dosage group when calculating.
As a result in each dosage group, the survival rate there was no significant difference of mice between experimental drug and contrast medicine group, the ED of this product treatment colon bacillus and klebsiella pneumoniae infecting mouse
50Be respectively 0.828mg/kg and 1.154mg/kg; The ED of contrast medicine prulifloxacin treatment colon bacillus and klebsiella pneumoniae infecting mouse
50Then be respectively 0.871mg/kg and 1.111mg/kg.Test shows: in mice, the prulifloxacin mesylate has obvious therapeutic effect to infecting due to colon bacillus, the klebsiella pneumoniae.
Claims (1)
1. the preparation method of a prulifloxacin mesylate is characterized in that step is as follows:
(1) preparation 3,4-two fluoro-dithio formic acid-aniline-triethylamine salts: under the nitrogen protection, the 129g difluoroaniline is placed the 1L reaction bulb, add the 202g triethylamine again, be cooled to 5 ℃, slowly drip 84g Carbon bisulfide, finish in 5～10 ℃, stirring reaction spends the night, filter, ether drip washing filter cake, the room temperature vacuum drying gets faint yellow solid namely;
(2) preparation 3; 4-difluorophenyl isothiocyanate: under the nitrogen protection; add successively in the 1L reaction bulb that 306g step (1) makes 3; 4-two fluoro-dithio formic acid-aniline-triethylamine salts; the 450mL dichloromethane stirs, and frozen water is cooled to 5 ℃; drip the 119g chloroformate acetate; finish in 5～10 ℃ of reactions 3 hours, in reactant impouring 500g mixture of ice and water, stir evenly; layering; water layer merges organic facies with dichloromethane 200mL extraction 3 times, respectively water and saturated common salt water washing; tell organic layer, add MgSO
4Drying removes by filter desiccant, concentrated filtrate, and 80～82 ℃/5mmHg fraction is collected in distilling under reduced pressure, gets faint yellow aqueous thing namely;
(3) preparation 6,7 two fluoro-4-oxos-2-ethylthio quinoline-3-carboxylic acid second fat: under nitrogen protection, in the 700mL dioxane that contains potassium hydroxide 53.4g, drip diethyl malonate 128g, in 35 degree reflections 2 hours, be down to room temperature, drip in 1 hour that step (2) makes in the reactant liquor 3,4-difluorophenyl isothiocyanate, and under this temperature, reacted 15 hours, filter, solid transfer drips the 87.2g bromoethane in about 0～5 ℃ to DMF500mL, react after 2 hours, be warming up to 60 ℃, reacted 5 hours, cold slightly, add 1.5L water and 300mL dichloromethane, water washs 2 times with dichloromethane 300mL, merge organic layer, organic layer is told in water 200mL washing 2 times, add the desiccant drying, filter, filtrate decompression concentrate faint yellow oily thing, residue adds the 500mL diphenyl ether, reaction is 30 minutes in outer temperature oil bath, diphenyl ether is removed in distilling under reduced pressure, and residual liquid adds normal hexane 500mL, cools off 0～5 ℃, separate out faint yellow crystallization, filter, with the normal hexane washing that contains 5% ethanol, vacuum drying namely;
(4) preparation 6,7 two fluoro-4-acetoxyl groups-2-ethylthio quinoline-3-carboxylic acid second fat: mix under nitrogen protection that 100g step (3) makes 6,7 two fluoro-4-oxos-2-ethylthio quinoline-3-carboxylic acid second fat, 400mL triethylamine and 1L dichloromethane, drip the 49g acetic anhydride under the ice-water bath and be cooled to 5 ℃, finish and stirred 3 hours, reactant liquor is poured in the frozen water, layering, water merges organic facies with dichloromethane 300ml extraction 3 times, and organic layer is told in washing, add the desiccant drying, the filtering desiccant concentrates and steams except dichloromethane, gets little yellow crystals powder namely;
(5) preparation (±) 6,7 two fluoro-1-methyl-4-oxo-4H-[1,3]-sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid second fat: with 80g step (4) make 6,7-two fluoro-4-acetoxyl groups-2-ethylthio quinoline-3-carboxylic acid second fat, the 500mL normal hexane places reaction bulb, drips the hexane solution 100mL of 65g sulfonic acid chloride under reflux state in 4 hours, finishes and continues to reflux 4 hours, evaporated under reduced pressure gets faint yellow oily thing, add 700mL oxolane and 108g anhydrous sodium acetate, refluxed 4 hours, be cooled to room temperature, pour in the 2L frozen water, separate out crystal, filter, be washed to neutrality, drying gets the light brown crystallization namely;
(6) preparation (±) 6,7 two fluoro-1-methyl-4-oxo-4H-[1,3]-sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid: under the nitrogen protection, with the 56g potassium hydroxide, the 600mL tert-butyl alcohol and 200mL water join in the reaction bulb stirring and dissolving, stir and add (±) 6 that 62.3g step (5) makes down, 7 two fluoro-1-methyl-4-oxo-4H-[1,3]-sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-carboxylic acid second fat also, refluxed 4 hours, add 800mL water, be neutralized to neutrality with the hydrochloric acid of 2mol/L, separate out precipitation, filter, filter cake washes with water, and vacuum drying gets little yellow crystalline powder, namely;
(7) preparation 4-(1-piperazine)-methyl-5-methyl isophthalic acid, 3-Er Evil cyclopentenes-2-ketone: under nitrogen protection, with the 4-bromomethyl-5-methyl isophthalic acid of 22.2g content 87%, 3-Er Evil cyclopentenes-2-ketone is dissolved among the 60mL DMF, the DMF solution 40mL that room temperature is dripped and added the 17.2g Piperazine anhydrous finishes in room temperature reaction 3 hours, adds 200mL water, with dichloromethane 100mL extraction 3 times, merge organic layer, add the desiccant drying, remove by filter desiccant, concentrated filtrate gets red solid namely;
(8) preparation 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1, the 3-Dioxol-4-yl)-methyl isophthalic acid-piperidyl]-4-oxo-4H-[1,3] the sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid: under nitrogen protection, (±) 6,7 two fluoro-1-methyl-4-oxo-4H-[1 that 42.5g step (6) is made, 3]-sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid, 30g potassium bicarbonate and 300mLDMF add in the reaction bulb, stirring at room half an hour, add 4-(1-piperazine)-methyl-5-methyl isophthalic acid that 49.6g step (7) makes again, 3-Er Evil cyclopentenes-2-ketone, stirring reaction 5 hours, in reactant liquor impouring 1L frozen water, adjust pH about 7.0, separate out precipitation, filter water washing, vacuum drying, the crude product thermosol is in the 1L acetonitrile, heat filtering, slowly crystallisation by cooling gets little yellow crystal, namely;
(9) preparation prulifloxacin mesylate: in the 1L three-necked bottle, add 10g prulifloxacin and 500mL acetonitrile, after dissolving half an hour is stirred in backflow, continue to stir and add methanesulfonic acid 2.70g down, stirred 30 minutes, and added 50mL distilled water and active carbon 1.0g, be warming up to backflow gradually, insulation 2h, react complete substantially, solution becomes must be clarified, filtered while hot, filtrate is put refrigerator cold-storage and is spent the night, separate out crystal, sucking filtration, twice of washing with alcohol of filter cake, each 25mL, the gained solid gets off-white color or light yellow solid, namely at 40 ℃ of following drying under reduced pressure 10h.
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Effective date of registration: 20170707 Address after: 310000 No. 258, No. 12, Hangzhou economic and Technological Development Zone, Zhejiang Patentee after: Hangzhou Guoguang pharmaceutical Limited by Share Ltd Address before: 310018 No. 258, No. twelve, Hangzhou economic and Technological Development Zone, Zhejiang Patentee before: Hu Dingguo |