CN101434611A - 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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- CN101434611A CN101434611A CN 200710031350 CN200710031350A CN101434611A CN 101434611 A CN101434611 A CN 101434611A CN 200710031350 CN200710031350 CN 200710031350 CN 200710031350 A CN200710031350 A CN 200710031350A CN 101434611 A CN101434611 A CN 101434611A
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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 3-((acetyloxy)methyl)-7-(Alpha-(N, N-bis (1-methylethyl)-thiourea) acetamido)-8-oxo-5-thia-1-azabicyclo (4, 2, 0)-octadiene-2-sodium carboxylate 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, blood poisoning, 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 microbiotic that a kind of nitrogen heterocyclic ring replaces, be particularly related to the 3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid sodium, sylvite and synthetic method and application.
Technical background
The chemistry of cephalo piperazine amidine by name (6R, 7R)-3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and oct-2-ene-2-carboxylic acid, be a kind of new cephalosporin compound, the structure of this compound is as follows:
Formula II compound is the cefathiamidine analogue of Chinese invention patent application number 200410050908.X initiative, 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 tangible pungency, can not be directly medicinal.
Because the amidine sulfenyl has alkalescence, easily form inner salt with 2 carboxyl on the cephalo parent 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 a 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 the 16th the 7th phase of volume of Acta Pharmaceutica Sinica 494 pages (1981), report 7-acetobrom amido cephalosporins derivatives 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 is studied and is prepared the cynnematin that contains the 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 the impurity height, color and luster is dark, and toxicity is big.And, be not mentioned to the preparation of its amine salt and hydrobromate in the patent for mentioning " described cephalo piperazine amidine chemical structure is a free acid form, also can be its hydrobromate or amine salt form " among the patent 200410050908.X.
The concrete synthetic method of having introduced cephalo piperazine amidine among the patent 200410050908.X is: acetobrom 7ACT and di-isopropyl thiourea carry out condensation reaction in halo alkanes, ketone, alcohols or their mixed solvent, and specification sheets also explains for the 6th～7 page again, and shows that the product purity that this 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,, cause product degradation as open loop with acid, soda finishing method destructible beta-lactam structure, the content of product can reduce on the contrary, and product stability is impacted.Adopt the dissolved method in addition in addition, but some impurity can not be removed still.
Summary of the invention
The microbiotic that the object of the present invention is to provide a kind of nitrogen heterocyclic ring to replace.
Another object of the present invention provides the preparation method of cephalo piperazine amidine an alkali metal salt; This method technology is simple, the product purity height.
A further object of the present invention provides the pharmaceutical composition that cephalo piperazine amidine an alkali metal salt is made active ingredient.
Technical solution of the present invention: the microbiotic that a kind of nitrogen heterocyclic ring replaces, comprise the 3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and oct-2-ene-2-carboxylic 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 microbiotic that above-mentioned nitrogen heterocyclic ring replaces wherein is preferably the compound of Ia structure:
Its chemistry is by name: the methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic 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, goes up the side chain triazine rings for 3 and the enol form tautomeric structure can take place and show its acidity, as follows 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, show in the intravital pharmacokinetics preliminary study of Beagle dog, 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 microbiotic 3-[(acetoxyl group that the nitrogen heterocyclic ring of general formula I structure replaces) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation method of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid sodium, sylvite is:
1, with the 3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid is dissolved or suspended in certain solvent system with sodium transforming agent or changes potassium agent reaction;
Described salifiable solvent system is selected from the mixed solvent of water, alkyl ketone, alkyl alcohol, alkyl nitrile, carboxylic acid amide or above-mentioned solvent.Alkyl is meant lower alkyl such as C1～12 alkane, preferred C1～4.
Described sodium transforming agent or the agent of commentaries on classics potassium, sodium transforming agent is selected from sodium alkoxide, sodium soap or aromatic acid sodium, the inorganic sodium that contains 1～5 carbon atom; As sodium methylate, sodium acetate, Sodium isooctanoate, sodium tartrate, sodium hydroxide, yellow soda ash, sodium bicarbonate; Changeing the potassium agent is selected from; Potassium hydroxide, salt of wormwood, saleratus.
In the described salt-forming reaction, when adding sodium transforming agent or changeing potassium agent and 7-acetobrom-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-when the mol ratio of Cephalosporanic acid is 1:1, become monometallic salt (as single sodium salt, monopotassium salt); When adding sodium transforming agent or changeing potassium agent and 7-acetobrom-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-when the mol ratio of Cephalosporanic acid is 2:1, become two metal-salts (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 apace reduces product content.So when changeing the sodium nak response, should be earlier with quick decentralized compound (II) under the rotating speed of r=200～500 rev/min such as solvent such as ethanol, acetonitrile etc., controlled temperature is below 40 ℃, adopt online particle test analytical instrument monitoring, otherwise drip precipitation agent such as acetone or alcohol in reaction soln the 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 new Compound I is a kind ofly not only to have better active antimicrobial compounds (seeing Table) to gram positive organism but also to some gram-negative bacterias;
The extracorporeal bacteria inhibitor test of table one: Compound I a, Ib, Ic is MIC as a result
90(mgL
-1)
| Bacteria name | Compound I a | Compounds ib | Compound I c |
| Enterococcus faecalis | 8 | 4 | 8 |
| Alpha streptococcus | 0.5 | 0.1 | 0.1 |
| Beta streptococcus | 0.0625 | 0.0125 | 0.0156 |
| Streptococcus pneumoniae | 0.125 | 0.5 | 0.5 |
| Hemophilus influenzae | 0.5 | 0.5 | 0.5 |
| Moraxelle catarrhalis | 1 | 0.5 | 0.5 |
| Shigella | 4 | 4 | 4 |
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.1 week back intersection administration at interval 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, and separated plasma, (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 to add extracting solution.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 LD of Ia vein and intramuscular injection
50With 95% credible being limited to: 0.9g/kg, similar to cefathiamidine.Carried out the research of Compound I a animal antibacterial activity in vivo, mouse infection enterococcus faecalis, streptococcus pneumoniae and moraxelle catarrhalis have all 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 high density and are tried thing in the quadriceps muscle of thigh of rabbit left side, tried thing in right lateral thigh four-head intramuscularly lower concentration.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 that 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 significant stimulation variations such as sex change in various degree.
As from the foregoing: the anti-microbial activity of Compound I 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 tangible 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℃ | 10℃ | 40℃ | 60℃ |
| II content, % | 98.0 | 97.9 | 96.3 | 92.75 |
| Ia content, % | 97.0 | 96.9 | 96.6 | 96.4 |
Open and related " the antibiotic an alkali metal salt that a kind of nitrogen heterocyclic ring replaces " preparation method that proposes of the present invention, those skilled in the art can be by using for reference this paper content, and 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 in 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 regarded as being 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, the product purity height.
Embodiment:
Embodiment 1:
Among the following embodiment, 7-acetobrom ACT is meant: 7-acetobrom-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) sulfo-] methyl]-Cephalosporanic acid.
One, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-preparation of oct-2-ene-2-carboxylic acid (II) (with reference to the preparation of Chinese invention patent 200410050908.X " amidine sulphur acetamido cynnematin, preparation method and application that C3 methylene radical nitrogen heterocyclic ring replaces " method)
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) and 4. restrain..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、1339
m/e：572
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic 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 quick stirring of changeing 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、1366
m/e：594
Ultimate analysis: C
21H
28N
7NaO
6S
3
The calculated value measured value
C：42.45％ 42.39％
H：4.72％ 4.94％
N：16.51％ 16.45％
S：16.17％ 16.13％
Sodium ion stratographic analysis: calculated value measured value
Na：3.87％ 3.99％
Embodiment 2:
One, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):
5 ℃, in there-necked flask, 0.1 gram yellow soda ash is dissolved among the deionized water 5ml, under stirring fast, per minute 500 commentaries on classics add compound (II) 1 gram, 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 98.35%, and 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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):
5 ℃, in there-necked flask, add above gained compound (II) 1 gram, deionized water 4ml, 95% ethanol 4ml, change being stirred to dissolving fully fast 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＝18)、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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):
0 ℃, in there-necked flask, 0.1 gram yellow soda ash is dissolved among the deionized water 5ml, under per minute 450 commentaries on classics high-speed stirring, add compound (II) 1 gram, 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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):
5 ℃, in there-necked flask, add above gained compound (II) 1 gram, deionized water 4ml, 95% ethanol 4ml, change high-speed stirring to dissolving fully 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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid-sodium salt (Ia):
0 ℃, in there-necked flask, add deionized water 3ml, acetonitrile 3ml, drop into compound (II) 1 gram and change dissolving fully 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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid disodium salt (Ib):
As example 1 operation, wherein substitute 0.3 gram Sodium isooctanoate and react with 0.6 gram Sodium isooctanoate, 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 calculated value measured value
C：40.93％ 41.11％
H：4.39％ 4.44％
N：15.92％ 16.01％
S：15.59％ 15.53％
The sodium ion stratographic analysis:
The calculated value measured value
Na：7.47％ 7.40％
Embodiment 8:
One, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid disodium salt (Ib):
As specific examples 7 operations, wherein substitute 0.1 gram yellow soda ash and react with 0.2 gram yellow soda ash.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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid one sylvite (Ic):
5 ℃, in there-necked flask, add deionized water 5ml, compound (II) 1 gram, salt of wormwood 0.15 gram, changeed 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 calculated value measured value
C：41.33％ 41.1％
H：4.59％ 4.65％
N：16.07％ 16.01％
S：15.75％ 15.70％
The potassium ion stratographic analysis:
The calculated value measured value
K：6.41％ 6.64％
Example 10:
One, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic 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, change 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, produces 7-acetobrom ACT with embodiment 1
Two, methyl 3-[(acetoxyl group)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-preparation of 8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid di-potassium (Id):
0 ℃, in there-necked flask, add deionized water 5ml, compound (II) 1 gram, salt of wormwood 0.3 gram, changeed 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 calculated value measured value
C：38.90％ 39.1％
H：4.17％ 4.35％
N：15.13％ 15.22％
S：14.82％ 15.07％
The potassium ion stratographic analysis:
The calculated value measured value
K：12.04％ 12.13％
Embodiment 12
The preparation of anti-infectives
One, produces 7-acetobrom ACT with embodiment 1
Two, with 5 ℃, in there-necked flask, add above gained compound (II) 100 grams, water for injection 400ml, 95% ethanol 400ml, change high-speed stirring to dissolving fully 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 0.5g/ bottle or 1.0g/ bottle specification, roll lid.
Embodiment 13 tablet preparation
Prescription
Per thousand consumptions of every consumption
Compound I 250mg 251g
Lactose 63.6mg 63.6g
Pregelatinized Starch 81.5mg 81.5g
Magnesium Stearate 4.1mg 4.1g
Preparation: get Compound I a, lactose and the pregelatinized Starch of embodiment 12 gained, mixed 15～30 minutes; Be tackiness agent with 10%PVP solution again, make particle, particle was in 50 ℃ of dryings 2 hours, and whole grain adds Magnesium Stearate, mixes, and is pressed into tablet.Get the plain sheet of gained, with 10%HPMC solution bag film-coat, packing.
Claims (8)
1, a kind of microbiotic of nitrogen heterocyclic ring replacement, it is characterized in that the 3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and oct-2-ene-2-carboxylic 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, methyl a kind of microbiotic 3-[(acetoxyl group of nitrogen heterocyclic ring replacement)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and the preparation method of oct-2-ene-2-carboxylic acid sodium, sylvite, its feature comprises:
(1), with the 3-[(acetoxyl group) methyl]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylic acid medicinal compound is dissolved or suspended in the salifiable solvent system with sodium transforming agent or changes potassium agent reaction;
(2), the product of gained is added precipitation agent, separate out, separate.
3, the methyl microbiotic 3-[(acetoxyl group of nitrogen heterocyclic ring replacement according to claim 2)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and the preparation method of oct-2-ene-2-carboxylic acid sodium, sylvite, described salifiable solvent system is selected from the mixed solvent of water, alkyl ketone, alkyl alcohol, alkyl nitrile, carboxylic acid amide or above-mentioned solvent.Alkyl is meant lower alkyl such as C1～12 alkane, preferred C1～4.
4, the methyl microbiotic 3-[(acetoxyl group of nitrogen heterocyclic ring replacement according to claim 2)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-preparation method of oct-2-ene-2-carboxylic acid sodium, sylvite, described sodium transforming agent or the agent of commentaries on classics potassium, sodium transforming agent is selected from sodium alkoxide, sodium soap or aromatic acid sodium, the inorganic sodium that contains 1～5 carbon atom; As sodium methylate, sodium acetate, Sodium isooctanoate, sodium tartrate, sodium hydroxide, yellow soda ash, sodium bicarbonate; Changeing the potassium agent is selected from; Potassium hydroxide, salt of wormwood, saleratus.
5, the methyl microbiotic 3-[(acetoxyl group of nitrogen heterocyclic ring replacement according to claim 2)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-and the preparation method of oct-2-ene-2-carboxylic acid sodium, sylvite, 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 methyl microbiotic 3-[(acetoxyl group of a kind of nitrogen heterocyclic ring replacement according to claim 2)]-7-[α-(N, N-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-preparation method of oct-2-ene-2-carboxylic acid sodium, sylvite, it is characterized in that in salt-forming reaction, when adding sodium transforming agent or changeing potassium agent and 7-acetobrom-3[((1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) methyl sulfo-)]-when the mol ratio of Cephalosporanic acid is 1:1, become monometallic salt, as single sodium salt, monopotassium salt; When its mol ratio is 2:1, become two metal-salts, as disodium salt, di-potassium.
7, the microbiotic that replaces according to the described nitrogen heterocyclic ring of claim 1 is at pharmaceutical composition that pharmaceutically can received vehicle.
8, the microbiotic that replaces according to the described nitrogenous nitrogen heterocyclic ring of claim 1 is used to prepare the purposes of anti-infectives.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110118462A1 (en) * | 2009-11-18 | 2011-05-19 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | N-heterocyclic substituent-containing antibiotic, preparation and use thereof |
| CN105461739A (en) * | 2014-09-09 | 2016-04-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | Crystalline (6R,7R)-3-[(acetoxyl)methyl]-7-[alpha-(N,N-diisopropyl amidinethio) acetamido]-8-oxo-thia-1-azabicyalo[4,2,0]- octyl-2-ene-2-carboxylic acid-sodium salt and preparation method therefor and use thereof |
| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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| CN1315845C (en) * | 2004-07-30 | 2007-05-16 | 广州白云山制药股份有限公司 | Methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, preparation method and application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110118462A1 (en) * | 2009-11-18 | 2011-05-19 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | N-heterocyclic substituent-containing antibiotic, preparation and use thereof |
| CN105461739A (en) * | 2014-09-09 | 2016-04-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | Crystalline (6R,7R)-3-[(acetoxyl)methyl]-7-[alpha-(N,N-diisopropyl amidinethio) acetamido]-8-oxo-thia-1-azabicyalo[4,2,0]- octyl-2-ene-2-carboxylic acid-sodium salt and preparation method therefor and use thereof |
| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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