CN101434611B - Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof - Google Patents
Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof Download PDFInfo
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- CN101434611B CN101434611B CN 200710031350 CN200710031350A CN101434611B CN 101434611 B CN101434611 B CN 101434611B CN 200710031350 CN200710031350 CN 200710031350 CN 200710031350 A CN200710031350 A CN 200710031350A CN 101434611 B CN101434611 B CN 101434611B
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- MGCGFOMPXPVARB-UHFFFAOYSA-N CN(C(SC)=NC1=O)N=C1O Chemical compound CN(C(SC)=NC1=O)N=C1O MGCGFOMPXPVARB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to an antibiotic substituted by nitrogen heterocyclic ring, and a preparation method and the application thereof, pertaining to the antibiotic medicament of a human body, and discloses the structural formula (I) of 7-(Alpha-(N, N-bis (1-methylethyl)-thiourea) acetamido)-3-(((2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1, 2, 4-triazine-3-base)sulfo)methyl)-cephalosporin polyhydroxyalkanoate sodium salt and sylvite, and a manufacturing method and the application thereof. The antibiotic has good antibacterial activity, can treat diseases caused by hypersensitive gram positive bacteria and gram negative bacteria, bloodpoisoning, alimentary infection, urinary tract infection, has long half-life of plasma and little toxicity and can reduce times for taking medicaments every day and treatment fees. The compound has good stability and is stored at normal temperature; the manufacturing method is simple; a product obtained by the manufacturing method has high purity and meets medical requirements.
Description
Technical field
The present invention relates to the cyclosubstituted microbiotic of a kind of nitrogen-containing hetero, be particularly related to 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid sodium, sylvite and synthetic method and application.
Technical background
The chemistry of cephalo piperazine amidine is called 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid, be a kind of new cephalosporin compound, the structure of this compound is as follows:
Formula II compound is the pioneering cefathiamidine analogue of Chinese invention patent application 200410050908.X, the part gram positive organism is had active preferably.
The present inventor finds, formula II compound water-soluble lower, and stability is poor, and pH value of water solution is 3.2, and muscle and blood vessel are had obvious pungency, can not be directly medicinal.
Because the amidine sulfenyl has alkalescence, easily form inner salt with 2 carboxyl on the cephalosporin nucleus, the cynnematin that therefore contains the amidine sulfenyl is its inner salt.By existing knowledge and bibliographical information, mention that in patent 200410050908.X described formula II compound chemical structure is free acid form, also can be its hydrobromate or amine salt form.The cefathiamidine of similar structures also is 2 formic acid betaines (referring to two ones 156 pages of Pharmacopoeia of People's Republic of China versions in 2005) forms; Wang Wenmei intends literary composition in Acta Pharmaceutica Sinica the 7th phase of the 16th volume 494 pages (1981), the amino cephalosporins derivatives of report 7-acetobrom and various substituting thioureido derivatives reaction, other cephalosporin derivatives of gained can be inner salt or free acid, also can be their hydrobromates; Chinese invention patent 03113688.5 has also prepared the amine salt of cefathiamidine, and is applied to the purifying of cefathiamidine; But without any document be mentioned to the preparation of hydrobromate.In sum, existing technology institute research and preparation contains the cynnematin of amidine sulfenyl, only relates to its these chemical structures of inner salt, free acid, hydrobromate or amine salt.
Synthetic method according to patent 200410050908.X report, the inventor furthers investigate discovery to formula II compound, because add excessive organic bases in the reaction, as the triethylamine that exemplifies, the cynnematin of the amidine sulfenyl of preparation can contain its triethylamine salt, the triethylamine salt of formula II compound draws moist strong, it is difficult to remove, and prepared formula II compound is actual to be the mixture that contains formula II compound triethylamine salt, thereby impurity is high, color and luster is dark, and toxicity is large.And for mentioning " described cephalo piperazine amidine chemical structure is free acid form, also can be its hydrobromate or amine salt form " among the patent 200410050908.X, be not mentioned to the preparation of its amine salt and hydrobromate in the patent.
The concrete synthetic method of having introduced cephalo piperazine amidine among the patent 200410050908.X is: 7-acetobrom ACT and di-isopropyl thiourea carry out condensation reaction in halo alkanes, ketone, alcohols or their mixed solvent, and the 6th～7 page in specification sheets also explains again, and shows that the product purity that the method draws reaches 90%.But if further improve product purity, general cephalosporin process for purification commonly used is the method for transferring iso-electric point with acid, alkali: and with acid, soda finishing method destructible beta-lactam structure, such as open loop, cause product degradation, the content of product can reduce on the contrary, and product stability is impacted.Adopt in addition in addition the dissolved method, but some impurity can not be removed still.
Summary of the invention
The object of the present invention is to provide the cyclosubstituted microbiotic of a kind of nitrogen-containing hetero.
Another object of the present invention provides the preparation method of cephalo piperazine amidine an alkali metal salt; The method technique is simple, and product purity is high.
A further object of the present invention provides the pharmaceutical composition that cephalo piperazine amidine an alkali metal salt is made active ingredient.
The invention provides the cyclosubstituted Antibiotique composition I of nitrogen-containing hetero and pharmaceutical composition that pharmaceutically can received vehicle.The present invention also provides the purposes of the cyclosubstituted microbiotic I of nitrogen-containing hetero for the preparation of anti-infectives.
Technical solution of the present invention: the cyclosubstituted microbiotic of a kind of nitrogen-containing hetero, comprise 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid sodium, sylvite, its general structure is:
Comprising:
Ia：Y＝H，Z＝Na；
Ib：Y＝Na，Z＝Na；
Ic：Y＝H，Z＝K；
Id：Y＝K，Z＝K。
The cyclosubstituted microbiotic of above-mentioned nitrogen-containing hetero wherein is preferably the compound of Ia structure:
Its chemistry is by name: 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid one sodium salt, soluble in water and the methyl alcohol of this compound is insoluble in dehydrated alcohol and acetone.
To containing the cynnematin structure of amidine sulfenyl, suc as formula this compounds of II, existing disclosed technology is just assert its these chemical structures of inner salt, free acid, hydrobromate or amine salt.The inventor analyzes according to its constructional feature, thinks that cephalo piperazine amidine has carboxyl and has the acidity except 2, and 3 upper side chain triazine rings the enol form tautomeric structure can occur and show its acidity, see following formula:
Therefore, even after cephalo piperazine amidine forms inner salt, still may continue to form an alkali metal salt, or even two mol alkali metal-salts.The inventor has carried out lot of experiments, studies the salify synthesis technique, has successfully obtained an alkali metal salt of formula II compound, has confirmed original imagination.A series of relevant studies of pharmacy have been carried out simultaneously, and be surprised to find that formula II compound an alkali metal salt has good using value, relatively cephalo piperazine amidine has not only strengthened water-soluble, and nonirritant, pharmacokinetics preliminary study in Beagle dog body shows, it is 2.59 hours that formula II compound an alkali metal salt blood is eliminated the transformation period, prolonged about 4 times in 0.65 hour than cefathiamidine, administration number of times is reduced, increase the conformability of patient's medication, in addition, compare with cephalo piperazine amidine, formula II compound an alkali metal salt compounds anti-microbial activity is good, plasma half-life is long, toxicity is low, good stability, can reduce medication every day number of times, reduce medical expense and can be used for treating responsive gram positive organism and the caused respiratory tract infection of gram-negative bacteria, wound and surgical infection, urinary tract infections, otorhinolaryngology infects, meningitis, pleuritis, endocarditis and septicemia, and lung, gastrointestinal tract infection, and can directly use, having fabulous clinical application meaning, is a novel cephalosporin analog antibiotic that DEVELOPMENT PROSPECT is arranged very much.
The cyclosubstituted microbiotic 7-[of the nitrogen-containing hetero of general formula I structure α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation method of Cephalosporanic acid sodium, sylvite is:
1, with 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid is dissolved or suspended in certain solvent system with sodium transforming agent or turns potassium agent reaction;
The solvent system of described salify is selected from the mixed solvent of water, alkyl ketone, alkyl alcohol, alkyl nitrile, carboxylic acid amide or above-mentioned solvent.Alkyl refers to lower alkyl such as C1～12 alkane, preferred C1～4.
Described sodium transforming agent or turn the potassium agent, sodium transforming agent is selected from sodium alkoxide, sodium soap or aromatic acid sodium, the inorganic sodium that contains 1～5 carbon atom; Such as sodium methylate, sodium acetate, Sodium isooctanoate, sodium tartrate, sodium hydroxide, yellow soda ash, sodium bicarbonate; Turning the potassium agent is selected from; Potassium hydroxide, salt of wormwood, saleratus.
In the described salt-forming reaction, when adding sodium transforming agent or turning the potassium agent and 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-mol ratio of Cephalosporanic acid is 1: 1 o'clock, becomes monometallic salt (such as single sodium salt, monopotassium salt); When adding sodium transforming agent or turning the potassium agent and 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-mol ratio of Cephalosporanic acid is 2: 1 o'clock, becomes two metal-salts (such as disodium salt, di-potassium).
2, the product with step 1 gained adds precipitation agent, separates.
Described precipitation agent is selected from the alcohol that contains 1～4 carbon atom, contain the ketone of 3～6 carbon atoms or the solvent mixture of one or two or more kinds wherein.
During salt-forming reaction, compound (II) is dissolved in the water, because acidity is stronger, degraded makes the product content rapidly.So when turning the sodium nak response, should be first with rapid dispersion compound (II) under the rotating speed of r=200～500 rev/min such as solvent such as ethanol, acetonitrile etc., the control temperature is below 40 ℃, adopt online particle test analytical instrument monitoring, otherwise drip the precipitation agent such as acetone or alcohol in the reaction soln time, product can not be separated out, and only goes out a large amount of oily matter, can't obtain solid.
To Compound I a, Ib, Ic with agar two-fold dilution method respectively to having carried out extracorporeal bacteria inhibitor test, be surprised to find that this novel compound I is a kind of not only to gram positive organism but also the antimicrobial compounds (seeing Table) that some gram-negative bacterias had better activity;
The extracorporeal bacteria inhibitor test of table one: Compound I a, Ib, Ic is MIC as a result
90(mgL
-1)
The present inventor has carried out preliminary pharmacokinetic studies to Compound I a with the Beagle dog.16h plays fasting in the 4h to the administration before the Beagle dog test, only freely drinks water.Respectively at behind the intravenous injection 50mg/kgbw sample 0,0.083,0.17,0.25,0.5,1,1.5,2,3,4,6,9,12h venous blood collection 3mL.Interval intersection administration after 1 week is by same time point venous blood collection.Blood sample places the plastic centrifuge tube that contains heparin, the centrifugal 10min of 4000rpm behind the mixing, separated plasma, the adding extracting solution (methyl alcohol: ethyl acetate=3: 2, V/V), behind the vibration mixing, the centrifugal 10min of 10000rpm gets supernatant liquor 20 μ L, carries out HPLC and measures.The result: healthy beagle dog single intravenous injection sample (Ia) (50mg/kgbw) after, Cmax is 116.35 ± 12.06 μ g/mL, the Plasma Concentration after 12 hours still can reach 0.39 ± 0.09 μ g/mL; T1/2 α is 0.63 ± 0.12h, shows that it distributes rapidly, and t1/2 β is 2.59 ± 0.04h, (0.65 ± 0.03h), AUC is 108.29 ± 18.17mg/Lh, and V1 is 0.25 ± 0.07L/kg obviously to be longer than cefathiamidine, VB is 1.61 ± 0.30L/kg, shows widely distributed; C1B is 0.47 ± 0.09L/kg/h.And acute toxicity test in mice shows: the intravenous LD of Ia
50Be 1.7476g/kg, toxicity is significantly less than cefathiamidine (LD
50Be 0.8242g/kg).Carried out the research of Compound I a animal antibacterial activity in vivo, mouse infection enterococcus faecalis, streptococcus pneumoniae and moraxelle catarrhalis have been had good provide protection.
The inventor has carried out the muscular irritation test to Compound I a and II.Rabbit muscle irritation test: test with 8 new zealand rabbits, be divided into 3 groups: Compound I a and each 3/group of II group, 2 of negative control group are injected the high density tested material, in right lateral thigh four-head intramuscularly lower concentration tested material in the quadriceps muscle of thigh of rabbit left side.Negative control group is injection equivalent sodium chloride injection in the quadriceps muscle of thigh of both sides all.Every side quadriceps muscle of thigh inner injecting and administering 1.0mL, once a day, for three days on end, each group is got 1～2 rabbit and cutd open inspection in 48 hours after the last administration, and remaining rabbit is cutd open inspection after 2 decubations in week of last administration finish.After the last administration 48 hours and 14 days, except Compound I a organizes in last administration 2 week decubation 1 rabbit visual inspection slightly the minimal irritation, Compound I I administration treated animal injection site muscle visual inspection result all sees the significant stimulation variations such as sex change in various degree.
As from the foregoing: the anti-microbial activity of Compound I a is good, plasma half-life is long, toxicity is low, can reduce medication every day number of times, reduce medical expense, be a novel cephalosporin analog antibiotic that DEVELOPMENT PROSPECT is arranged very much, can be used for treating responsive gram positive organism and the caused respiratory tract infection of gram-negative bacteria, wound and surgical infection, urinary tract infections, otorhinolaryngology infection, meningitis, pleuritis, endocarditis and septicemia, and lung, gastrointestinal tract infection.
Compare with II, I has better stability (seeing Table two) in the aqueous solution, has obvious stability advantage (seeing Table three) at solid-state Ia, and therefore, this compound can need not freezing or special processing just can be preserved before the deadline.From commercial point of view, the formula Ia compound of this high stability is very superior.
Table two in the time of 37 ℃, Compound I I, Compound I a and the Ib content in injection water
Table three Compound I I and Compound I a preserve the content after 72 hours under differing temps
| Temperature | -5℃ | l0℃ | 40℃ | 6℃ |
| II content, % | 98.0 | 97.9 | 96.3 | 92.75 |
| Ia content, % | 97.0 | 96.9 | 96.6 | 96.4 |
Open and related " the cyclosubstituted antibiotic an alkali metal salt of a kind of nitrogen-containing hetero " preparation method that proposes of the present invention, those skilled in the art can be by using for reference this paper content, and the links such as appropriate change raw material, processing parameter, structure design realize.Product of the present invention and method are described by preferred embodiment, person skilled obviously can be within not breaking away from content of the present invention, spirit and scope to method as herein described with product is changed or suitably change and combination, realize the technology of the present invention.Special needs to be pointed out is, the replacement that all are similar and change apparent to those skilled in the artly, they are deemed to be included in the present invention.
The invention has the beneficial effects as follows that anti-microbial activity is good, can treat responsive gram positive organism and the caused disease of gram-negative bacteria, septicemia, lung, gi tract, urinary tract infection, plasma half-life is long, toxicity is low, can reduce medication every day number of times, reduces medical expense, compound stability of the present invention is good, normal temperature is preserved, and manufacture method of the present invention is simple, and product purity is high.
Embodiment:
Embodiment 1:
Among the following embodiment, 7-acetobrom ACT refers to: 7-acetobrom amino-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid.
One, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation (with reference to the preparation of Chinese invention patent 200410050908.X " the cyclosubstituted amidine thiacetamides of C3 methylene radical nitrogen-containing hetero base cynnematin, preparation method and application " method) of Cephalosporanic acid (II)
There-necked flask adds methylene dichloride 100ml, 7-acetobrom ACT 4.9 grams (0.01mol), be added dropwise to triethylamine 2.8ml (0.02mol) makes it dissolving, adds N, N-di-isopropyl thiourea 2.4 grams (0.015mol), and 30 ℃ of reactions are to fully; Stir after 1 hour, lowered the temperature 1 hour; Suction filtration, vacuum-drying get compound (II) 4 grams.Content (HPLC) is 94.3%.
The pH=3.2 of its saturated aqueous solution.
1HNMR(DMSO-d
6，400Hz)：1.16(m，12H，J＝6)、3.34(d，1H，J＝17.5)、3.63(d，1H，J＝17.5)、3.57(s，3H)、3.94(m，4H)、4.13(d，1H，J＝13)、4.33(d，1H，J＝13)、5.04(d，1H，J-5)、5.57(q，1H)、9.42(d，1H，J＝7.5)IR(KBr，cm
-1)：1783、1657、1606、1411、1339m/e：572
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia): 0 ℃, in there-necked flask, add deionized water 5ml, Sodium isooctanoate 0.3 gram, compound (II) 1 gram, acetone 5ml, the rapid stirring that turns at per minute 350 45 minutes adds decolorizing with activated carbon, filters, filtrate is dripped in the 60ml acetone, adopt online particle test analytical instrument monitoring, separate out precipitation, filter, wash 2 times with acetone, 40 ℃ of (Vanadium Pentoxide in FLAKES) vacuum-dryings get compound (Ia) 0.75 gram.Content (HPLC) is 98.76%.
1HNMR(DMSO-d
6，500Hz)：1.13(m，12H，J＝6)、3.34(d，1H，J＝17.5)、3.56(d，1H，J＝17.5)、3.51(s，3H)、3.87(m，4H)、4.15(d，1H，J＝13)、4.32(d，1H，J＝13)、4.99(d，1H，J＝5)、5.50(q，1H)、9.35(d，1H，J＝7.5)IR(KBr，cm
-1)：1767、1605、1498、1403、1366m/e：594
Ultimate analysis: C
21H
28N
7NaO
6S
3
Sodium ion stratographic analysis: calculated value measured value
Na：3.87％ 3.99％
Embodiment 2:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia):
5 ℃, in there-necked flask, 0.1 gram yellow soda ash is dissolved among the deionized water 5ml, turn at per minute 500 and add compound (II) 1 gram under the rapid stirring, reacted 45 minutes, and added decolorizing with activated carbon, filter, filtrate drips in the 80ml acetone, adopt online particle test analytical instrument monitoring, separate out solid, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Ia) 0.75 gram in 24 hours, and content (HPLC) is that 98.35%, pH is 7.3 (concentration is 0.1g/ml).
1HNMR(DMSO-d
6，500Hz)：1.12(m，12H，J＝6)、3.35(d，1H，J＝17.5)、3.57(d，1H，J＝17.5)、3.50(s，3H)、3.77(m，4H)、4.14(d，1H，J＝13)、4.37(d，1H，J＝13)、4.99(d，1H，J＝5)、5.50(q，1H)、9.32(d，1H，J＝7.5)
Embodiment 3:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia):
5 ℃, in there-necked flask, add above gained compound (II) 1 gram, deionized water 4ml, 95% ethanol 4ml, turn rapid stirring to fully dissolving at per minute 200, splash into 8% sodium bicarbonate 1.8ml, reacted 30 minutes, add decolorizing with activated carbon, filtration drips to filtrate in the 100ml acetone, adopts online particle test analytical instrument monitoring, separate out solid, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Ia) 0.7 gram in 24 hours.Content (HPLC) is 98.81%.
1HNMR(D
2O，400Hz)：1.25(m，12H，J＝6.4)、3.45(d，1H，J＝18)、3.69(d，1H，J＝1g)、3.62(s，3H)、3.98(m，4H)、4.07(d，1H，J＝13.6)、4.32(d，1H，J＝13.6)、5.12(d，1H，J＝5)、5.56(d，1H，J＝4.5)。
Embodiment 4:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia):
0 ℃, in there-necked flask, 0.1 gram yellow soda ash is dissolved among the deionized water 5ml, turn at per minute 450 and add compound (II) 1 gram under the high-speed stirring, pH is 7.2; Reacted 45 minutes, and added decolorizing with activated carbon, filter, filtrate is dripped in the 100ml ethanol, adopt online particle test analytical instrument monitoring, separate out solid, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings get compound (Ia) 0.65 gram.Content (HPLC) is 98.09%.
1HNMR result is with example 2.
Embodiment 5:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia):
5 ℃, in there-necked flask, add above gained compound (II) 1 gram, deionized water 4ml, 95% ethanol 4ml, turn high-speed stirring to fully dissolving at per minute 450, splash into 8% sodium bicarbonate 1.8ml, reacted 30 minutes, and added decolorizing with activated carbon, filter, 60ml acetone is dripped in the filtrate, adopt online particle test analytical instrument monitoring, separate out solid, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings get compound (Ia) 0.7 gram.Content (HPLC) is 98.50%.
1HNMR result is with example 2.
Embodiment 6:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sodium salt (Ia):
0 ℃, in there-necked flask, add deionized water 3ml, acetonitrile 3ml, drop into compound (II) 1 gram and turn fully dissolving under the high-speed stirring at per minute 250; Slowly splash into 2% sodium hydroxide 3.5ml, stirred 45 minutes, add decolorizing with activated carbon, filter, filtrate is dripped in the 100ml acetone, adopt online particle test analytical instrument monitoring, separate out precipitation, filter, wash 2 times with acetone, 40 ℃ of (Vanadium Pentoxide in FLAKES) vacuum-dryings get compound (Ia) 0.65 gram.Content (HPLC) is 97.12%.
Embodiment 7:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid disodium salt (Ib):
Such as example 1 operation, wherein substitute 0.3 gram Sodium isooctanoate with 0.6 gram Sodium isooctanoate and react, 40 ℃ of vacuum-dryings of product got compound (Ib) 0.76 gram in 24 hours; Content (HPLC) is 96.72%.
m/e：616；
Ultimate analysis: C
21H
27N
7Na
2O
6S
3
The sodium ion stratographic analysis:
The calculated value measured value
Na：7.47％ 7.40％
Embodiment 8:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid disodium salt (Ib):
Such as specific examples 7 operations, wherein substitute 0.1 gram yellow soda ash with 0.2 gram yellow soda ash and react.40 ℃ of vacuum-dryings of products therefrom got compound (Ib) 0.8 gram in 24 hours; Content (HPLC) is 96.33%.
PH is 10.02 (concentration is 0.1g/ml).
Sodium ion stratographic analysis: C
21H
27N
7Na
2O
6S
3
The calculated value measured value
Na：7.47％ 7.59％
Example 9:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sylvite (Ic):
5 ℃, in there-necked flask, add deionized water 5ml, compound (II) 1 gram, salt of wormwood 0.15 gram, turned high-speed stirring 30 minutes at per minute 400, add decolorizing with activated carbon, filter, filtrate is dripped in the 160ml acetone, adopt online particle test analytical instrument monitoring, separate out precipitation, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Ic) 0.73 gram in 24 hours.Content (HPLC) is 97.43%.
Ultimate analysis: C
21H
28KN
7O
6S
3
The potassium ion stratographic analysis:
The calculated value measured value
K：6.41％ 6.64％
Example 10:
One, produce 7-[α [(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid one sylvite (Ic):
5 ℃, adding deionized water 5ml, compound (II) 1 gram, 95% ethanol 5ml dissolve fully in there-necked flask, add saleratus 0.17 gram, turn high-speed stirring 30 minutes at per minute 450, add decolorizing with activated carbon, filter, filtrate is dripped in the 160ml acetone, adopt online particle test analytical instrument monitoring, separate out precipitation, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Ic) 0.67 gram in 24 hours.Content (HPLC) is 97.1%.
The potassium ion stratographic analysis:
The calculated value measured value
K：6.41％ 6.29％
Example 11:
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-preparation of Cephalosporanic acid di-potassium (Id):
0 ℃, in there-necked flask, add deionized water 5ml, compound (II) 1 gram, salt of wormwood 0.3 gram, turned high-speed stirring 45 minutes at per minute 350, add decolorizing with activated carbon, filter, filtrate is dripped in the 200ml acetone, adopt online particle test analytical instrument monitoring, separate out the white throw out of class, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Id) 0.85 gram in 24 hours.Content (HPLC) is 97.03%.
Ultimate analysis: C
21H
27K
2N
7O
6S
3
The potassium ion stratographic analysis:
The calculated value measured value
K：12.04％ 12.13％
Embodiment 12
The preparation of anti-infectives
One, produce 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid (II) is with embodiment 1
Two, with 5 ℃, in there-necked flask, add above gained compound (II) 100 grams, water for injection 400ml, 95% ethanol 400ml, turn high-speed stirring to fully dissolving at per minute 200, splash into 8% sodium bicarbonate 180ml, reacted 30 minutes, and added the pin decolorizing with activated carbon, filter decarburization; 0.45 μ m membrane filtration is used 0.22 μ m membrane filtration, again under the clean environment condition, filtrate is dripped in 101 acetone, adopt online particle test analytical instrument monitoring, separate out throw out, filter, wash 2 times with acetone, 40 ℃ of vacuum-dryings got compound (Ia) 68 grams in 24 hours, pulverized, and measured content and moisture, under aseptic condition, be distributed into 0.05g/ bottle or 1.0g/ bottle specification, roll lid.
The preparation of embodiment 13 tablets
Prescription
Preparation: get Compound I a, lactose and the pregelatinized Starch of embodiment 12 gained, mixed 15～30 minutes; Again take 10%PVP solution as tackiness agent, granulation, particle was in 50 ℃ of dryings 2 hours, and whole grain adds Magnesium Stearate, mixes, and is pressed into tablet.Get gained element sheet, with 10%HPMC solution film coating, packing.
Claims (8)
1. the cyclosubstituted microbiotic of nitrogen-containing hetero is characterized in that 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid sodium, sylvite, its general structure is:
Comprising:
Ia：Y＝H，Z＝Na；
Ib：Y＝Na，Z＝Na；
Ic：Y＝H，Z＝K；
Id：Y＝K，Z＝K。
2. the cyclosubstituted antibiotic preparation method of a kind of nitrogen-containing hetero according to claim 1, its feature comprises:
(1), with 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid is dissolved or suspended in the solvent system of salify with sodium transforming agent or turns potassium agent reaction;
(2), the product of gained is added precipitation agent, separate out, separate.
3. the cyclosubstituted antibiotic preparation method of a kind of nitrogen-containing hetero according to claim 2, the solvent system of described salify is selected from the mixed solvent of water, alkyl ketone, alkyl alcohol, alkyl nitrile or above-mentioned solvent, and alkyl refers to contain the alkyl of C1～4.
4. the cyclosubstituted antibiotic preparation method of a kind of nitrogen-containing hetero according to claim 2, described sodium transforming agent or turn the potassium agent, sodium transforming agent is selected from sodium methylate, sodium acetate, Sodium isooctanoate, sodium tartrate, sodium hydroxide, yellow soda ash, sodium bicarbonate; Turning the potassium agent is selected from; Potassium hydroxide, salt of wormwood, saleratus.
5. the cyclosubstituted antibiotic preparation method of a kind of nitrogen-containing hetero according to claim 2, described precipitation agent is selected from the alcohol that contains 1～4 carbon atom, contain the ketone of 3～6 carbon atoms or the solvent mixture of one or two or more kinds wherein.
6. the cyclosubstituted antibiotic preparation method of a kind of nitrogen-containing hetero according to claim 2, it is characterized in that in salt-forming reaction, when adding sodium transforming agent or turning the potassium agent and 7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-mol ratio of Cephalosporanic acid is 1: 1 o'clock, becomes monometallic salt, described monometallic salt is single sodium salt or monopotassium salt; When its mol ratio is 2: 1, become two metal-salts, described two metal-salts are disodium salt or di-potassium.
7. contain the cyclosubstituted microbiotic of the described nitrogen-containing hetero of claim 1 and pharmaceutical composition that pharmaceutically can received vehicle.
According to claim 1 the cyclosubstituted microbiotic of described nitrogen-containing hetero for the preparation of the purposes of anti-infectives.
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