CN102838621A - (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals - Google Patents
(6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals Download PDFInfo
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Abstract
The invention relates to (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine, crystals thereof, and preparation method and application thereof. According to the invention, 7-ADCA and bromoacetyl bromide are subjected to a reaction, such that an intermediate A, which is 7-bromo acetylamino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- alkene-2-formic acid, is obtained; the intermediate A is subjected to a reaction with N'N-diisopropyl thiourea, such that the compound provided by the invention is obtained. The compound is further refined, such that the crystals of the compound with high purity and good stability are prepared. The compound provided by the invention has antibacterial effects against escherichia coli, staphylococcus aureus, streptococcus pneumoniae, Hay enterococci, enterococcus faecalis, and the like. Especially, the compound has a high inhibiting activity against streptococcus pneumoniae. The compound is a potential antimicrobial medicine.
Description
Technical field
The invention belongs to chemical pharmacy field; More specifically, relate to a kind of cephalosporin compound, its crystal, particularly relate to (6R; 7R)-3-methyl-7-[α-(N; N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine crystal.
Background technology
Hu Min and Hu Changqin use degraded product (Hu Min, the Hu Changqin that the LC-MS method has been analyzed cefathiamidine; " the LC-MS method is analyzed the cefathiamidine degraded product "; Acta Pharmaceutica Sinica Acta Pharmaceutica Sinica2006,41 (10): 1015-1019, confirm that 2 main degradation products are the hydrolysate of cefathiamidine; Be respectively deacetylate cefathiamidine and cefathiamidine lactone, its structural formula is following:
The deacetylate cefathiamidine
The cefathiamidine lactone
People such as Ye Fang also adopt the LC-MS method to analyze the degraded product of cefathiamidine (Ye Fang etc.; " LC-MS of cefathiamidine degraded product analyzes "; China's microbiotic magazine, the 30th the 12nd phase of volume of December in 2005,741-743); Point out that cefathiamidine mainly contains two degraded products-go acetyl cefathiamidine and cephalo ester amidine (promptly being respectively above-mentioned deacetylate cefathiamidine and cefathiamidine lactone), the generative process of two main degradation products is following:
The inventor is engaged in the production and the research work of cefathiamidine for a long time; In the impurity of analysis and research cefathiamidine; Be surprised to find that compound (6R, 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4; 2,0]-(its molecular formula is C to oct-2-ene-2-formic acid betaine
17H
26N
4O
4S
2, structural formula is following, the hereinafter referred compound I) be one of major impurity in the typical HPLC collection of illustrative plates of cefathiamidine:
Compound I
The inventor discovers that cefathiamidine as the not obviously increase of compound I of impurity, therefore infers that compound I is not the degraded product of cefathiamidine under failure conditions such as acid, alkali, heating or under the long-term storage condition.Starting raw material, side reaction equal angles are started with from the cefathiamidine building-up process, find that compound I wherein is that following series reaction takes place the major impurity 7-ADCA among the starting raw material 7-ACA, produces compound I at last in the preparation cefathiamidine process:
Compound I
Adopt and the similar compound method of cefathiamidine; Shown in top reaction formula; With 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid is that 7-ADCA (7-ADCA also is a common major impurity among the preparation cefathiamidine starting raw material 7-ACA) is a starting raw material, and 7-ADCA and bromoacetyl bromide reaction obtain 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (being intermediate A), this intermediate A and the reaction of N ' N-di-isopropyl thiourea; Obtain (6R; 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2; 0]-oct-2-ene-2-formic acid betaine, i.e. compound I.But resulting compound I is Powdered, and purity is not high, and compound I has the unique molecular structure of zwitter-ion inner salt, meets thermally labile, needs through further refining to obtain stability crystal preferably.
Summary of the invention
Therefore; Order of the present invention is to provide (6R; 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2; 0]-oct-2-ene-2-formic acid betaine (being compound I) and preparation method thereof; Step two phase process through simple prepares midbody 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (being intermediate A), and intermediate A and N ' N-di-isopropyl thiourea reaction then obtains compound I;
Another object of the present invention is to compound I crystal that provides a kind of good stability and preparation method thereof;
A purpose more of the present invention provides above-claimed cpd I and the purposes of crystal in preparation human or antibacterials for animals thereof; Said compound I and crystal thereof to streptococcus aureus, streptococcus pneumoniae, Hai Shi faecalis, enterococcus faecalis, intestinal bacteria, etc. have antibacterial effect, might can be used for respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia, meningitic treatment.
According to an aspect of the present invention; The present invention provides a kind of cephalosporin compound; Be structural formula following (6R, 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4; 2,0]-oct-2-ene-2-formic acid betaine (abbreviation compound I):
Compound I
According to a further aspect in the invention, the present invention provides a kind of compound I crystal of good stability, uses Cu-K α radiation, and this crystal has following X-ray powder diffraction pattern:
Wherein, 2 θ are diffraction angle, and d is a spacing, I/I
0Be relative intensity, above-mentioned X-ray powder diffraction pattern is represented more than or equal to 5% peak with relative intensity.
According to the present invention, the present invention provides a kind of preparation method of compound I, and this method comprises the steps:
Compound I
Step 1: utilize two phase process; Under alkaline condition; The reaction of 7-ADCA (being 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid) and bromoacetyl bromide obtains that 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid is intermediate A; With
Step 2: in the presence of triethylamine, intermediate A and the reaction of N ' N-di-isopropyl thiourea obtain (6R; 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2; 0]-oct-2-ene-2-formic acid betaine, i.e. compound I.
In above-mentioned steps 1, after 7-ADCA is dissolved in the water under alkaline condition, add and the immiscible solvent of water, under 120～300 rev/mins of stirrings of rotating speed, add bromoacetyl bromide, under 0～40 ℃, reacted 1～3 hour; After reaction finishes, tell water, with pH to 1.0～4.0 of acid adjusting water, intermediate A is separated out; The mol ratio of wherein said 7-ADCA and bromoacetyl bromide is 1: 1～1.5, and said alkali is triethylamine, sodium hydrogencarbonate or yellow soda ash, with the immiscible solvent of water be benzene, toluene, ether, methylene dichloride or chloroform, said acid is sulfuric acid, hydrochloric acid or phosphoric acid.
In above-mentioned steps 2; Intermediate A is dissolved under the triethylamine effect, and intermediate A and N ' N-di-isopropyl thiourea mol ratio are 1: 1～1.5, and the reaction solvent for use is chloroform, methylene dichloride, methyl alcohol, ethanol, acetone or its mixture; Temperature of reaction is 10～50 ℃, 1～4 hour reaction times.
Like the said compound I that obtains of above-mentioned preparation method is white to the micro-yellow powder shape, and purity 90～93% needs further refining to prepare the good compound I crystal of purity high stability.Compound I is dissolved with polar solvent; Obtain the solution of compound I, at a certain temperature, through in the solution of compound I, add dissolve each other with above-mentioned polar solvent and with compound I slightly soluble or insoluble crystallization solvent; Control saturation history and crystalline growth velocity; Obtain required compound I crystallization,, obtain the compound I crystal at last through separation, drying.
Therefore; The present invention provides a kind of purity high stability good compound I crystalline preparation method; This method comprises: adopt the polarity dissolution solvent that compound I is dissolved, obtain compound I solution, wherein said polarity dissolution solvent is water, lower alcohol or its mixture; Perhaps said polarity dissolution solvent is water and/or lower alcohol and acetone according to volume ratio 5～100: 1 mixture, the concentration of compound I are 0.05～0.5g/ml; Then, 0～45 ℃ of temperature, under 20～150 rev/mins of stirrings of stirring velocity; It is muddy slightly to occurring to drip for the first time the crystallization solvent; Growing the grain 0.5～2 hour continues to drip crystallization solvent to a large amount of crystal for the second time and separates out filtration drying; Obtain the compound I crystal, wherein said crystallization solvent is ketone or ketone and ethanol according to volume ratio 0.5～100: 1 mixture;
Wherein said lower alcohol comprises methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol and isopropylcarbinol etc.; Said ketone comprises acetone, methylethylketone and pentanone etc.
In compound I crystalline preparation method according to the present invention; Wherein said polarity dissolution solvent is preferably: water, methyl alcohol, water/carbinol mixture; Methyl alcohol and/or water and ethanol is 0.2～100: 1 mixture by volume; Methyl alcohol and/or water and acetone is 5～100: 1 mixture by volume, methyl alcohol, ethanol and acetone by volume 0.2～100: 1～10: 1 mixture, and perhaps water, ethanol and acetone by volume 0.2～100: 1～10: 1 mixture;
Said crystallization solvent is acetone or acetone and ethanol according to volume ratio 1～100: 1 mixture.
Temperature is very big to the influence of the size of crystalline particle in the crystallization process, selects suitable temperature, help obtaining hope big or small crystal; And can therefrom control uniform particles property; Said temperature is 0～45 ℃, is preferably 0～30 ℃, more preferably 8～20 ℃.
In whole crystallisation process, factors such as degree of supersaturation, crystallization speed, stirring velocity have material impact to final crystallization.Degree of supersaturation control and temperature, the amount and the rate of addition that drip the crystallization solvent for the first time are relevant; Crystallization speed and degree of supersaturation, the control of crystallization solvent rate of addition for the second time are relevant; Stirring velocity has material impact to the size of crystalline particle.When dripping the crystallization solvent, stirring velocity is changeed at PM 20～150, and preferred 20～40 change, and speed control should be avoided local oversaturated formation, avoids oarse-grained crystal to be destroyed again.The amount of crystallization solvent adding for the first time is good can just make system separate out small amount of crystal, and the dropping time is controlled at 1～2h.Behind the growing the grain 0.5～2 hour, when separating out than polycrystal, drip the crystallization solvent for the second time, the dropping time is controlled at 1～3h.The amount of crystallization solvent can be adjusted according to the concentration of compound I residual in the mother liquor behind the suction filtration for the second time, and this relates to the comprehensive assessment problem of yield and crystallization solvent cost, can adjust as required.The amount of crystallization solvent is little to the influence of crystalline form size for the second time.
Above-mentioned crystallization method is batch crystallization, continuous crystallisation etc. no matter, can implement
Compound I of the present invention and crystal thereof have antibacterial effect to streptococcus aureus, streptococcus pneumoniae, Hai Shi faecalis, intestinal bacteria, enterococcus faecalis etc., might can be used for respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, the meningitic treatment of pneumonia.The compound I crystal of embodiment 5 preparations below adopting is used " disinfection technology standard " 2002 editions 2.1.8.4 minimal inhibitory concentrations method and is carried out antibacterial tests, and the result is as shown in the table:
The invention has the advantages that:
(1) The compounds of this invention I crystal stability is good, and purity is high;
(2) compound I of the present invention and crystal thereof have antibacterial effect to intestinal bacteria, streptococcus aureus, streptococcus pneumoniae, Hai Shi faecalis, enterococcus faecalis etc., and be especially very strong to the streptococcus pneumoniae anti-microbial activity, is the potential antibacterials.
Description of drawings
Fig. 1 is the compound I crystalline X-ray powder diffraction pattern of the embodiment of the invention 5 preparations.
Embodiment
Through embodiment the present invention is described more specifically below, but protection scope of the present invention is not limited among the following embodiment.
One. the preparation of compound I
Embodiment 1: preparation 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (intermediate A)
At room temperature, in 300ml water, add 30g (0.14mol) 7-ADCA, under 120 rev/mins of stirrings, slowly drip triethylamine and dissolve fully to 7-ADCA, obtain settled solution.In above-mentioned settled solution, add methylene dichloride 50ml, adjust the temperature to 0～5 ℃, drip sodium hydrogen carbonate solution (24g is dissolved in 250ml water) and drip 15ml bromoacetyl bromide (0.17mol).Be incubated 0～5 ℃, reaction 30～60min, standing demix is told water, slowly drips the 3mol/L sulphuric acid soln to this aqueous phase, and 0～5 ℃ of temperature maintenance when pH about 3 begins to separate out solid, is about 1.0～1.5 to be titration end point until pH, continues growing the grain 1h.Suction filtration, filter residue washing three times, vacuum-drying obtains the intermediate A of about 39g.
Embodiment 2: the preparation intermediate A
At room temperature, in 500ml water, add 30g (0.14mol) 7-ADCA, under agitation drip sodium hydrogen carbonate solution (27.6g is dissolved in 250ml water) and dissolve fully to 7-ADCA, obtain settled solution.In above-mentioned settled solution, add toluene 100ml, adjust the temperature to 30～35 ℃, continue to drip the sodium hydrogen carbonate solution and dropping 18ml bromoacetyl bromide (0.21mol) of above-mentioned remainder.Be incubated 30～35 ℃, reaction 30～60min, standing demix; Tell water, this water temperature regulation to room temperature, is slowly dripped 3mol/L hydrochloric acid to this aqueous phase; When pH about 3 begins to separate out solid, be about 1.0～1.5 to be titration end point until pH, continue growing the grain 1h.Suction filtration, filter residue washing three times, vacuum-drying obtains about 36g intermediate A.
Embodiment 3: the preparation compound I
The 500ml methylene dichloride is adjusted the temperature to 15～20 ℃, add intermediate A 25g (0.075mol), slowly drip triethylamine to intermediate A and dissolve fully; Obtain settled solution; Then add N, N-di-isopropyl thiourea 14g (0.0875mol) slowly adjusts the temperature to 20～25 ℃.Reaction 2h, suction filtration, filter residue is with washed with dichloromethane 3 times.Room temperature vacuum-drying obtains the about 19g of compound I at last.Color and luster＜YG2 (being made into the aqueous solution of 0.1g/ml), adopting the HPLC method to measure purity is 91.8%.
Embodiment 4: the preparation compound I
The 600ml methylene dichloride is adjusted the temperature to 20～25 ℃, add intermediate A 25g (0.075mol), slowly drip triethylamine to intermediate A and dissolve fully; Obtain settled solution; Then add N, N-di-isopropyl thiourea 15g (0.09375mol) slowly adjusts the temperature to 20～25 ℃.Reaction 1h, suction filtration, filter residue is with washed with dichloromethane 3 times.Room temperature vacuum-drying obtains the about 18g of compound I at last.Color and luster＜YG2 (being made into the aqueous solution of 0.1g/ml), adopting the HPLC method to measure purity is 92.2%.
Two. the preparation of compound I crystalline
Embodiment 5
At normal temperatures, in there-necked flask, add 90ml methanol/ethanol mixed solution (1: 2 by volume), add the compound I bullion 30g of the foregoing description 3 preparations; After treating its dissolving; Adjust the temperature to 15～20 ℃, regulate about 40 rev/mins of stirring velocitys, slowly drip acetone mixed solution (5: 1 by volume) to muddy (about 1 hour) just occurring; Growing the grain 30 minutes; After separating out than polycrystal, continue to drip above-mentioned acetone mixed solution (5: 1 by volume), add acetone 540ml (about 2 hours) altogether at last altogether.Suction filtration with suitable acetone mixed solution (by volume 5: 1) washing 2 times, is drained, and drying under reduced pressure obtains compound I crystal 2 1g, adopts the HPLC method to measure purity 98%.
The compound I of the above-mentioned embodiment that obtains 3 and the compound I crystal of embodiment 5 are carried out freezer (sample is sealed in cillin bottle) reserved sample observing, investigate the variation of its color and luster and content, the result is following:
The result shows that compound I crystal color stability is good, and impurity does not obviously increase under storage condition, and good stability obviously is superior to the compound I without recrystallization.
Use the D/max-3A X-ray diffractometer, testing conditions is Cu scar K α
1Ray, voltage 35kv, electric current 25mA, 1 ° of emission slit, 1 ° of anti-scatter slit receives slit 0.3mm, 2 θ scopes: 3 °～50 °, 10 °/min, carry out X-ray diffraction analysis, Fig. 1 is the compound I crystalline X-ray powder diffraction figure of present embodiment preparation.
Use Bruker AVANCE AV400 superconduction pulse fourier transform nmr spectrometer that the compound I crystal of present embodiment preparation is carried out nuclear magnetic resonance spectroscopy, data and resolving as follows:
1H nuclear magnetic resonance spectrum data and parsing
13C nuclear magnetic resonance spectrum data and analysis
Embodiment 6
Under 10～15 ℃, in there-necked flask, add 60ml methyl alcohol, add the compound I bullion 30g of the foregoing description 4 preparations; After treating its dissolving, adjust the temperature to 15～20 ℃, regulate about 80 rev/mins of stirring velocitys; Slowly drip ethanol/acetone mixed solution (1: 1 by volume) and muddy (about 1 hour) just occurred, growing the grain 30 minutes is after separating out than polycrystal; Continue to drip, add ethanol/acetone mixed solution (1: 1 by volume) 480ml (about 2.5 hours) at last altogether.Suction filtration with the washing with acetone of appropriate amount 2 times, is drained, and drying under reduced pressure obtains compound I crystal 2 0g, purity 98.8%, and its X-ray powder diffraction figure is with embodiment 5.
Embodiment 7
Under 0～5 ℃, in there-necked flask, add 60ml water/methanol/ethanol (1: 1: 4 by volume), add the bullion 30g of the foregoing description 3 preparations; After treating its dissolving, 5～10 ℃ of attemperation are regulated about 80 rev/mins of stirring velocitys; Slowly drip ethanol/acetone mixed solution (1: 3 by volume) and muddy (about 1 hour) just occurred; Growing the grain 30 minutes after separating out than polycrystal, continues to drip ethanol/acetone mixed solution (1: 3 by volume) 480ml (about 2 hours) again.Suction filtration with the washing with acetone of appropriate amount 2 times, is drained, and drying under reduced pressure obtains compound I crystal 2 3g, purity 98.5%, and its X-ray powder diffraction figure is with embodiment 5.
Embodiment 8
Under 10～15 ℃, in there-necked flask, add 90ml water/ethanol/acetone (1: 5: 1 by volume), add the bullion 30g of the foregoing description 3 preparations; After treating its dissolving, 15～20 ℃ of attemperation are regulated about 80 rev/mins of stirring velocitys; Slowly drip acetone and muddiness (about 1.5 hours) just occurred; Growing the grain 30 minutes after separating out than polycrystal, continues to drip acetone 450ml (about 3 hours) again.Suction filtration with the washing with acetone of appropriate amount 2 times, is drained, and drying under reduced pressure obtains compound I crystal 2 0g, purity 98.2%, and its X-ray powder diffraction figure is with embodiment 5.
Claims (10)
1. (6R, 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine, its structural formula is following:
2. one kind (6R, 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4; 2; 0]-and oct-2-ene-2-formic acid betaine crystal, use Cu-K α radiation, this crystal X-ray powder diffraction pattern is as shown in Figure 1.
3. one kind (6R, 7R)-preparation method of 3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine, this method comprises the steps:
Compound I
Step 1: utilize two phase process; Under alkaline condition; 7-ADCA is the reaction of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid and bromoacetyl bromide, obtains that 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid is intermediate A; With
Step 2: in the presence of triethylamine, intermediate A and the reaction of N ' N-di-isopropyl thiourea obtain (6R; 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2; 0]-oct-2-ene-2-formic acid betaine, i.e. compound I.
4. preparation method according to claim 3 is characterized in that, in said step 1; After 7-ADCA is dissolved in the water under alkaline condition, add and the immiscible solvent of water, under 120～300 rev/mins of stirrings of rotating speed; Add bromoacetyl bromide, under 0～40 ℃, reacted 1～3 hour; After reaction finishes, tell water, with pH to 1.0～4.0 of acid adjusting water, intermediate A is separated out; The mol ratio of wherein said 7-ADCA and bromoacetyl bromide is 1: 1～1.5, and said alkali is triethylamine, sodium hydrogencarbonate or yellow soda ash, with the immiscible solvent of water be benzene, toluene, ether, methylene dichloride or chloroform, said acid is sulfuric acid, hydrochloric acid or phosphoric acid.
5. according to claim 3 or 4 described preparing methods; It is characterized in that in said step 2, intermediate A is dissolved under the triethylamine effect; Intermediate A and N ' N-di-isopropyl thiourea mol ratio are 1: 1～1.5; The reaction solvent for use is chloroform, methylene dichloride, methyl alcohol, ethanol, acetone or its mixture, and temperature of reaction is 10～50 ℃, 1～4 hour reaction times.
6. one kind (6R, 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4; 2,0]-and oct-2-ene-2-formic acid betaine crystalline preparation method, this method comprises: adopt the polarity dissolution solvent with (6R; 7R)-3-methyl-7-[α-(N; N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine is the compound I dissolving; Obtain compound I solution; Wherein said polarity dissolution solvent is water, lower alcohol or its mixture, and perhaps said polarity dissolution solvent is water and/or lower alcohol and acetone according to volume ratio 5～100: 1 mixture, the concentration of compound I are 0.05～0.5g/ml; Then, 0～45 ℃ of temperature, under 20～150 rev/mins of stirrings of stirring velocity; It is muddy slightly to occurring to drip for the first time the crystallization solvent; Growing the grain 0.5～2 hour continues to drip crystallization solvent to a large amount of crystal for the second time and separates out filtration drying; Obtain the compound I crystal, wherein said crystallization solvent is ketone or ketone and ethanol according to volume ratio 0.5～100: 1 mixture;
Wherein said lower alcohol is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol and the isopropylcarbinol; Said ketone is selected from acetone, methylethylketone and the pentanone.
7. preparation method according to claim 6 is characterized in that, said polarity dissolution solvent is: water; Methyl alcohol; Water/carbinol mixture, methyl alcohol and/or water and ethanol is 0.2～100: 1 mixture by volume, and methyl alcohol and/or water and acetone is 5～100: 1 mixture by volume; Methyl alcohol, ethanol and acetone by volume 0.2～100: 1～10: 1 mixture, perhaps water, ethanol and acetone by volume 0.2～100: 1～10: 1 mixture;
Said crystallization solvent is acetone or acetone and ethanol according to volume ratio 1～100: 1 mixture.
8. according to claim 6 or 7 described preparing methods, it is characterized in that the amount that the said first time, the crystallization solvent added is just making system separate out small amount of crystal, the dropping time is controlled at 1～2h; Behind the growing the grain 0.5～2 hour, when separating out than polycrystal, drip the crystallization solvent for the second time, the dropping time is controlled at 1～3h.
9. according to claim 6,7 or 8 described preparing methods, it is characterized in that said (6R; 7R)-3-methyl-7-[α-(N; N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine makes as follows:
Compound I
Step 1: utilize two phase process; Under alkaline condition; 7-ADCA is the reaction of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid and bromoacetyl bromide, obtains that 7-acetobrom amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid is intermediate A; With
Step 2: in the presence of triethylamine, intermediate A and the reaction of N ' N-di-isopropyl thiourea obtain (6R; 7R)-3-methyl-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2; 0]-oct-2-ene-2-formic acid betaine, i.e. compound I.
10. (6R; 7R)-3-methyl-7-[α-(N; N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4; 2,0]-oct-2-ene-2-formic acid betaine or the purposes of its crystal in preparation human or antibacterials for animals, the particularly purposes in the antibacterials of the anti-streptococcus pneumoniae of preparation.
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| CN201110169820.XA CN102838621B (en) | 2011-06-22 | 2011-06-22 | (6R,7R)-3-methyl-7-[alpha-(N,N'-diisopropyl amidine thio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-alkene-2-formic betaine crystals |
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| CN102838621A true CN102838621A (en) | 2012-12-26 |
| CN102838621B CN102838621B (en) | 2014-09-10 |
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| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1640878A (en) * | 2004-12-27 | 2005-07-20 | 托新权 | Method for preparing cefathiamidide |
| CN101704827A (en) * | 2009-08-18 | 2010-05-12 | 海南美大制药有限公司 | Novel route for cefathiamidine compounds |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1640878A (en) * | 2004-12-27 | 2005-07-20 | 托新权 | Method for preparing cefathiamidide |
| CN101704827A (en) * | 2009-08-18 | 2010-05-12 | 海南美大制药有限公司 | Novel route for cefathiamidine compounds |
Non-Patent Citations (1)
| Title |
|---|
| 胡敏等: ""LC-MS法分析头孢硫脒降解产物"", 《药学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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Address after: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the same road No. 78 Patentee after: White Cloud Mountain chemical pharmaceutical factory of Guangzhou Baiyunshan Pharmaceutical Group Co., Ltd. Patentee after: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD., BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address before: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the same road No. 78 Patentee before: Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Patentee before: Baiyunshan Pharmaceutical General Factory, Baiyunshan Pharmaceutical Co., Ltd, G |