CN102643293A - Cefdinir ternary complex and method for preparing cefdinir by using same - Google Patents
Cefdinir ternary complex and method for preparing cefdinir by using same Download PDFInfo
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Abstract
The invention discloses an intermediate compound shown as a formula II and used for preparing cefdinir, a preparation method for the intermediate compound and a method for preparing the cefdinir by using the intermediate. Through the compound, the cefdinir for preparation production can be prepared without secondary refining, wherein the content of the cefdinir is over 98 percent.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of midbody compound of cephalosporins medicine and be used to prepare the method for cephalosporins medicine, specifically be meant the cefdinir ternary complex and be used to prepare the method for cefdinir.
Background technology
Cefdinir is the oral broad spectrum antibiotic of third generation cephalosporin class; Be widely used in the pathogenic microbial infection of the various sensitivities of treatment clinically; Chemical name is 7-(Z)-[2-(thiazolamine-4-yl)-2-oxyimino acetylamino]-3-cephalo-obtusilic acid, and structure is suc as formula shown in the I:
The synthetic route of cefdinir mainly contains two kinds in the suitability for industrialized production at present; A kind of is the cefdinir side-chain acid that adopts trityl as protecting group; Promptly (Z)-2-(thiazolamine-4-yl)-2-triphen methoxyimino acetate (2-mercaptobenzothiazole) ester (BAEM) carries out condensation with 7-amino-3-vinyl (7-AVCA); Condensation product directly is hydrolyzed under acidic conditions, and crystallization prepares cefdinir.Reaction process is following:
。
Another kind is the cefdinir side-chain acid that adopts the ethanoyl protection; Promptly (Z)-2-(thiazolamine-4-yl)-2-acetyl oxyimino group thioacetic acid (S-2-benzothiazole) ester (CAEM) carries out condensation with 7-AVCA; Condensation product directly is hydrolyzed under alkaline condition; Crystallization obtains cefdinir.Reaction process is following:
The cefdinir content that these two kinds of preparing methods obtain is lower; Often do not reach medicinal standard, need secondary refining just can be used for the production of preparation, owing to make with extra care the significantly reduction that can cause product yield; Therefore above-mentioned two kinds of preparing methods' production cost is higher, and the economic benefit that is produced is lower.
Chinese patent CN1628118 discloses a kind of cefdinir midbody, this intermediates preparation, and this midbody is used to prepare the method for cefdinir.Said cefdinir midbody is trityl cefdinir An DMAC, and wherein, A is sulfuric acid or methylsulfonic acid, and n=2 or 3, DMAC are DMAC N,Ns.This midbody is at N by the cefdinir side-chain acid active ester of trityl as protecting group and 7-AVCA; In the N-N,N-DIMETHYLACETAMIDE after the condensation; Adding sulfuric acid or methylsulfonic acid and suitable anti-solvent obtain, and the midbody that obtains removes the protection base under certain condition and obtains cefdinir.The content of the cefdinir that technician of the present invention prepares according to the said method of this patent needs secondary refining just can meet Chinese Pharmacopoeia (2010 editions) cefdinir content and must not be less than 94.0% requirement about 90%.
Chinese patent CN1512996 discloses a kind of cefdinir crystallization hydrochlorate and has been used to prepare the method for cefdinir.Said crystallization hydrochlorate is cefdinir vitriol or cefdinir mesylate, and 2 DMAC are raw material by trityl cefdinir tosic acid, in solvent, obtains with formic acid-sulfuric acid mixture or formic acid-methylsulfonic acid mixture reaction.This crystallization hydrochlorate can obtain cefdinir with alkali reaction in solvent.
Disclose the trityl cefdinir among the WO2004/056835 and handled, obtained the phosphoric acid composite of cefdinir, obtained the method for cefdinir after making with extra care through peroxophosphoric acid.
Summary of the invention
One of technical problem to be solved by this invention provides a kind of cefdinir ternary complex (II) and preparation method thereof, x=0.5 ~ 1 wherein, and y=0.5 ~ 1.5,
Two of technical problem to be solved by this invention provides by cefdinir ternary complex (II) and sets out, and prepares the method for high purity cefdinir (I),
Therefore, one aspect of the present invention provides the cefdinir ternary complex shown in a kind of formula II:
Wherein, x=0.5 ~ 1, y=0.5 ~ 1.5, preferred x=1, y=1.
One aspect of the present invention also provides the preparation method of a kind of cefdinir ternary complex (II); Use trityl cefdinir methylsulfonic acid DMAc mixture (V) to be raw material, in organic solvent, earlier with phosphatase reaction, again with sulfuric acid reaction; Or directly and phosphoric acid, vitriolic mixture reaction; Or directly with formic acid, vitriolic mixture reaction, or direct and acetate, vitriolic mixture reaction obtain
Wherein, Ph is a phenyl, and DMAc is a DMAC N,N, n=2 ~ 3.
The preparation method of above-mentioned cefdinir ternary complex (II), said organic solvent is acetonitrile, ETHYLE ACETATE, methylene dichloride, preferred acetonitrile.
Said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:5 ~ 15 with the weightmeasurement ratio of organic solvent.
Said vitriolic mass concentration is 90 ~ 100%.
Said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.2 ~ 0.5 with the vitriolic weight ratio.
The mass concentration of said phosphoric acid is 70 ~ 90%.
Said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.5 ~ 1 with the weight ratio of phosphoric acid.
The mass concentration of said formic acid or acetate is 80 ~ 100%.
Said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.5 ~ 1.5 with the weight ratio of formic acid or acetate.
Said being reflected under 10 ~ 40 ℃ of conditions carried out, and the reaction times is 10 ~ 24h.
The present invention provides a kind of preparation method of cefdinir on the other hand, is raw material with cefdinir ternary complex (II), adds water earlier and stirs, and adding alkali adjusting pH value then is 6 ~ 8, and adding acid for adjusting pH value is 1.5 ~ 3, and crystallization obtains cefdinir (I),
The preparation method of above-mentioned cefdinir, the weight ratio of said water and cefdinir ternary complex (II) is 5 ~ 30:1.
Said alkali is two or more mixture of a kind of or arbitrary proportion in ammoniacal liquor, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium-acetate, the triethylamine.
The said alkali that adds is regulated pH value preferred 6.8 ~ 7.5.
Said acid is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate.
The said acid for adjusting pH value preferred 2.0 ~ 2.5 that adds.
The process that the preparation process of cefdinir ternary complex according to the invention (II) and being used to prepares cefdinir (I) is following:
The present invention prepares cefdinir ternary complex (II) raw materials used trityl cefdinir methylsulfonic acid DMAc mixture (V) can be by trityl cefdinir side chain active ester (III) and 7-AVCA at N; In the N-N,N-DIMETHYLACETAMIDE, under organic bases exists condensation reaction takes place and make.Reaction process is following:
Cefdinir sulfuric acid methylsulfonic acid ternary complex provided by the invention (II); In its preparation process; Because this ternary complex can be separated out with solid form when generating; Therefore can avoid the destruction of acidic medium, thereby reduce the generation of cefdinir E-configurational isomer, can obtain highly purified cefdinir ternary complex (II) the cephalo parent nucleus.When using the cefdinir ternary complex to prepare cefdinir; Though just through alkali dissolve, routine operation such as acid out prepared cefdinir, the result is unexpected, the content of the cefdinir that obtains is more than 98%; And purity is higher than 99%; E-configurational isomer content is less than 0.1%, and all other indexs all meet the requirement of 2010 editions standards of pharmacopoeia, need not to carry out the production that secondary refining both can be used for preparation.Not not with an organic solvent, only adopted water in the preparation process, significantly reduced pollution environment.
Description of drawings
Fig. 1 is embodiment 1 a gained sample
1The H-NMR spectrogram.
Fig. 2 is embodiment 2 gained samples
1The H-NMR spectrogram.
Fig. 3 is embodiment 3 gained samples
1The H-NMR spectrogram.
Fig. 4 is embodiment 1 a gained sample
13The C-NMR spectrogram.
Fig. 5 is embodiment 2 gained samples
13The C-NMR spectrogram.
Fig. 6 is embodiment 3 gained samples
13The C-NMR spectrogram.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation.
The preparation of embodiment 1 cefdinir methylsulfonic acid sulfuric acid ternary complex (II)
Trityl cefdinir methylsulfonic acid DMAc mixture (V) 36.7g, ETHYLE ACETATE 290mL are added in the reaction flask, stir adding 85% phosphoric acid 29.4g down, stir 10min, be warming up to 40 ℃, insulated and stirred reaction 6h.Be cooled to 20-25 ℃, add the 20% sulfuric acid acetonitrile solution that contains 98% sulfuric acid 7.4g, room temperature continues to stir 2h.Be cooled to 0-5 ℃, stir 2h, suction filtration, with the acetonitrile washing, vacuum-drying obtains white solid 16.9g to constant weight, and it is 98.3% that HPLC detects purity.
The preparation of embodiment 2 cefdinir methylsulfonic acid sulfuric acid ternary complexs (II)
The cooling of 750mL acetonitrile below 10 ℃, is added 80% phosphoric acid 70.3g and 95% sulfuric acid 27.6g under stirring successively, stir, add trityl cefdinir methylsulfonic acid DMAc mixture (V) 75g, 25 ℃ of stirring reaction 18h.Lower the temperature 0-5 ℃, stirring and crystallizing 2h filters, and with acetonitrile 70mL thorough washing, vacuum-drying obtains white solid 39.5g to constant weight, and it is 98.6% that HPLC detects purity.
The preparation of embodiment 3 cefdinir methylsulfonic acid sulfuric acid ternary complexs (II)
Trityl cefdinir methylsulfonic acid DMAc mixture (V) 25g, acetonitrile 200mL are mixed, be cooled to below 15 ℃, stir 10min, add 88% formic acid 15g, 98% sulfuric acid 7.5g, stirring at room reaction 18h.Lower the temperature 0-5 ℃, stirring and crystallizing 3h filters, and uses the acetonitrile thorough washing, and vacuum-drying obtains white solid 13.4g to constant weight, and it is 98.4% that HPLC detects purity.
Confirming of embodiment 4 cefdinir ternary complex (II) components
Get embodiment 1, embodiment 2, embodiment 3 gained samples respectively and measure corresponding sample 1, sample 2, the sample 3 of being numbered.
(1) liquid phase chromatography is confirmed the content of cefdinir in the sample
With reference to the content assaying method of cefdinir in the Chinese Pharmacopoeia 2010 editions, reference substance is that Chinese pharmaceutical biological product ltd provides.Utilize external standard method to record the percentage composition of cefdinir in the sample, the result is as shown in table 1:
Table 1
| Lot number | Peak area | Content % |
| Sample 1 | 4448840 | 69.93 |
| Sample 2 | 4540855 | 67.31 |
| |
4497154 | 67.26 |
(2) chemical titration is confirmed the ratio of cefdinir and sulfuric acid number in the sample
Utilize sulfate radical to generate sedimentary method and carry out precipitation titration, confirm the ratio of sulfuric acid in entire sample with bariumchloride.Measuring method takes by weighing about 2.5 grams of sample, places the 250mL Erlenmeyer flask; Add 50 milliliters in water, ultrasonic echography 20 minutes filters; Filtrating is with the barium chloride solution deposition of 0.1M, and sedimentation and filtration, filter cake are put 90 ℃ of dry 3h of baking oven; Weigh, confirm cefdinir and sulfuric acid number ratio in conjunction with the content of cefdinir.The result is as shown in table 2:
Table 2
| Lot number | Sample weighting amount (g) | Precipitation capacity (g) | Cefdinir and sulfuric acid number ratio |
| Sample 1 | 2.5144 | 0.757 | 1:0.72 |
| Sample 2 | 2.503 | 1.0205 | 1:1.03 |
| |
2.5028 | 0.8981 | 1:1.18 |
(3) proton nmr spectra
Testing tool: Bruker 500M type high score rate superconduction nuclear magnetic resonance spectrometer
Test foundation: " Modern Analytical Instrument analytical procedure general rule and measurement verification regulations " (JY/T 007-1996)
Testing method: each about 20mg of sample thief places the nuclear-magnetism pipe respectively, with 0.5ml DMSO dissolving, in 25 ℃ of following specimen of temperature control
1The H spectrum
Test result is following:
Sample 1:
1H-NMR (DMSO) δ: 6.957 (1H, d), 6.923 (2H, s), 6.900 (1H, s), 5.815 (1H, s), 5.634-5.352 (2H, dd), 5.235 (2H, d), 2.080 (3H, s) (Fig. 1)
Sample 2:
1H-NMR (DMSO) δ: 6.958 (1H, d), 6.923 (2H, s), 6.900 (1H, s), 5.814 (1H, s), 5.635-5.352 (2H, dd), 5.236 (2H, d), 2.079 (3H, s) (Fig. 2)
Sample 3:
1H-NMR (DMSO) δ: 6.957 (1H, d), 6.923 (2H, s), 6.900 (1H, s), 5.809 (1H, s), 5.634-5.351 (2H, dd), 5.236 (2H, d), 2.075 (3H, s) (Fig. 3)
Utilize in the hydrogen spectrum on the cefdinir ratio of methyl proton quantity on the proton and methylsulfonic acid, the cefdinir and the molecule number ratio of methylsulfonic acid that calculate in sample 1,2 and 3 are respectively 1:0.97,1:0.94 and 1:0.79;
(4) carbon-13 nmr spectra
Testing tool: Bruker 500M type high score rate superconduction nuclear magnetic resonance spectrometer
Test foundation: " Modern Analytical Instrument analytical procedure general rule and measurement verification regulations " (JY/T 007-1996)
Testing method: each about 20mg of sample thief places the nuclear-magnetism pipe respectively, with 0.5ml DMSO dissolving, in 25 ℃ of following specimen of temperature control
13The C spectrum
Test result is following:
Sample 1:
13C-NMR (DMSO) δ: 170.747,163.771,163.637,161.856,144.198,133.051,132.341,125.850,125.342,118.594,109.258,59.444,57.947,23.698 (Fig. 4)
Sample 2:
13C-NMR (DMSO) δ: 170.838,163.789,161.834,144.102,132.362,125.878,125.408,118.626,109.335,59.487,57.997,23.735 (Fig. 5)
Sample 3:
13C-NMR (DMSO) δ: 170.887,163.786,163.676,161.797,144.021,132.617,132.367,125.884,125.442,118.632,109.379,59.505,58.000,23.748 (Fig. 6)
(5) mass spectrum
Testing tool: Shimadzu LC-MS 2010EV System liquid chromatography mass logotype appearance (day island proper Tianjin), 25 ℃ of temperature, relative humidity 50%
Test condition: electron spray ionisation source (ESI), positive ion detects, methanol-water (80:20); Sweep limit 50 ~ 600 instrumental errors are 0.5
Test result: m/z396,418,434 its corresponding be [M+H]
+, [M+Na]
+, [M+K]
+,, conform to the cefdinir molecular weight analyte with theoretical value 395.41 basically identicals.Because of sample contains amino, under the ESI ionizer, be easy to detect the positive ion signal that it combines a proton or sodium ion or potassium ion, result verification, measured is the mass spectrum of cefdinir.
The preparation of embodiment 5 cefdinir methylsulfonic acid sulfuric acid ternary complexs (II)
The cooling of 600mL acetonitrile below 10 ℃, is added 90% phosphatase 24 4.4g and 100% sulfuric acid 20g under stirring successively, stir, add trityl cefdinir methylsulfonic acid DMAc mixture (V) 40g, 40 ℃ of stirring reaction 10h.Lower the temperature 0-5 ℃, stirring and crystallizing 2h filters, and with acetonitrile 50mL thorough washing, vacuum-drying obtains white solid 17.8g to constant weight, and it is 98.4% that HPLC detects purity.
Method according among the embodiment 4 detects products obtained therefrom, confirms as cefdinir methylsulfonic acid sulfuric acid ternary complex, and wherein cefdinir is 1:0.69 with vitriolic number ratio, and the number of cefdinir and methylsulfonic acid is than being 1:0.67.
The preparation of embodiment 6 cefdinir methylsulfonic acid sulfuric acid ternary complexs (II)
The cooling of 120mL acetonitrile below 10 ℃, is added 70% phosphatase 11 4.3g and 90% sulfuric acid 4.4g under stirring successively, stir, add trityl cefdinir methylsulfonic acid DMAc mixture (V) 20g, 10 ℃ of stirring reaction 24h.Lower the temperature 0-5 ℃, stirring and crystallizing 2h filters, and with acetonitrile 30mL thorough washing, vacuum-drying obtains white solid 11g to constant weight, and it is 98.3% that HPLC detects purity.
Method according among the embodiment 4 detects products obtained therefrom, confirms as cefdinir methylsulfonic acid sulfuric acid ternary complex, and wherein cefdinir is 1:0.62 with vitriolic number ratio, and the number of cefdinir and methylsulfonic acid is than being 1:0.82.
The preparation of embodiment 7 cefdinir methylsulfonic acid sulfuric acid ternary complexs (II)
The cooling of 120mL methylene dichloride below 10 ℃, is added trityl cefdinir methylsulfonic acid DMAc mixture (V) 20g, add 90% acetate 12g and 98% sulfuric acid 6g successively under stirring, stirring at room reaction 24h.Lower the temperature 0-5 ℃, stirring and crystallizing 2h filters, and with acetonitrile 30mL thorough washing, vacuum-drying obtains white solid 10.5g to constant weight, and it is 97.4% that HPLC detects purity.
Method according among the embodiment 4 detects products obtained therefrom, confirms as cefdinir methylsulfonic acid sulfuric acid ternary complex, and wherein cefdinir is 1:1.22 with vitriolic number ratio, and the number of cefdinir and methylsulfonic acid is than being 1:0.94.
Liquid chromatography, chemistry titration, proton nmr spectra and carbon through to the foregoing description gained sample is composed, mass spectral research; Assert and supply test agent to be cefdinir and methylsulfonic acid and vitriolic mixture; And the ratio of cefdinir and methylsulfonic acid is between 0.5-1.0 in the confirmatory sample, and cefdinir and vitriolic ratio are between 0.5-1.5.
The preparation of embodiment 8 cefdinirs
In the 500ml four-hole bottle, add the 150ml purified water, 10～15 ℃ of temperature controls add cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 15g that embodiment 1 obtains under stirring; Regulate pH to 7.0 with 10%NaOH solution, after the stirring and dissolving, add the 1g gac; Stirring at room decolouring 30min filters.It is 5.0 that filtrating uses 18% hydrochloric acid to transfer filtrating pH, and 40～45 ℃ of temperature controls stir at a slow speed down, and continuing to use 18% hydrochloric acid to transfer pH is 3.0, stirs 30min, and using 18% hydrochloric acid to transfer pH again is 2.5, stirs 1h, and temperature control stirs growing the grain 1h for 20～25 ℃ subsequently, and 0～5 ℃ is stirred growing the grain 1h.Suction filtration, with 25ml * 2 purified water washing, suction filtration, vacuum-drying gets cefdinir 10.8g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3.
The preparation of embodiment 9 cefdinirs
Cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 30g that embodiment 2 is obtained is suspended in the 900ml purified water, and 20～25 ℃ of temperature controls are regulated pH to 6.0 with 5% ammonia soln, after the stirring and dissolving, adds the 2g gac, stirs decolouring 1h, filters.It is 4.5 that filtrating uses 10% hydrochloric acid to transfer filtrating pH, 20～25 ℃ of temperature controls, and continuing to use 10% hydrochloric acid to transfer pH is 2.5, growing the grain 30min.Using 10% hydrochloric acid to transfer pH again is 1.5, stirs 1h at a slow speed.Temperature control stirs growing the grain 1h, 0～5 ℃ of stirring growing the grain 1h for 20～25 ℃ subsequently, and suction filtration is with 45ml * 2 purified water washing.Drain, vacuum-drying gets cefdinir 20.8g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3.
The preparation of embodiment 10 cefdinirs
Cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 12g that embodiment 3 is obtained is suspended in the 60ml purified water, and 15～20 ℃ of temperature controls are regulated pH to 8.0 with 15% sodium carbonate solution, after the stirring and dissolving, adds the 1g gac, stirs decolouring 30min, filters.It is 6.0 that filtrating uses 15% sulfuric acid to transfer filtrating pH, 25～30 ℃ of temperature controls, and continuing to use 15% sulfuric acid to transfer pH is 4.0, stirs 30min.Using 15% sulfuric acid to transfer pH again is 3.0, stirs 1h at a slow speed.Be cooled to 20～25 ℃ and stir growing the grain 1h, 0～5 ℃ of stirring growing the grain 1h, suction filtration is with 20ml * 2 purified water washing.Drain, vacuum-drying gets cefdinir 9.2g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3.
The preparation of embodiment 11 cefdinirs
Cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 15g that embodiment 5 is obtained is suspended in the 250ml purified water, and 25～30 ℃ of temperature controls are regulated pH to 6.8 with triethylamine, after the stirring and dissolving, adds the 1g gac, stirs decolouring 1h.Filter, using 20% acetic acid soln to transfer filtrating pH is 4.8,30～35 ℃ of temperature controls, and continuing to use 20% acetic acid soln to transfer pH is 3.5, growing the grain 30min.Using 20% acetic acid soln to transfer pH again is 2.0, stirs 1h at a slow speed.Be cooled to 20～25 ℃ and stir 1h, 0～5 ℃ of stirring 1h, suction filtration is with 25ml * 2 purified water washing.Drain, vacuum-drying gets cefdinir 10.3g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3.
The preparation of embodiment 12 cefdinirs
Cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 10g that embodiment 6 is obtained is suspended in the 200ml purified water, and 20～25 ℃ of temperature controls are regulated pH to 7.5 with 8% Pottasium Hydroxide, after the stirring and dissolving, adds the 0.8g gac, stirs decolouring 1h.Filter, it is 5.5 that filtrating uses 5% formic acid solution to transfer filtrating pH, 35～40 ℃ of temperature controls, and continuing to use 5% formic acid solution to transfer pH is 3.5, growing the grain 30min.Using 5% formic acid solution to transfer pH again is 1.8, stirs 1h at a slow speed.Be cooled to 20～25 ℃ and stir 1h, 0～5 ℃ of stirring 1h, suction filtration is with 15ml * 2 purified water washing.Drain, vacuum-drying gets cefdinir 6.7g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3.
The preparation of embodiment 13 cefdinirs
Cefdinir methylsulfonic acid sulfuric acid ternary complex (II) 10g that embodiment 7 is obtained is suspended in the 135ml purified water, and 15～20 ℃ of temperature controls are regulated pH to 7.2 with 10% sodium-acetate, after the stirring and dissolving, adds the 0.8g gac, stirs decolouring 1h.Filter, it is 5.0 that filtrating uses 5% phosphoric acid solution to transfer filtrating pH, 35～40 ℃ of temperature controls, and continuing to use 5% phosphoric acid solution to transfer pH is 3.5, growing the grain 30min.Using 5% phosphoric acid solution to transfer pH again is 1.5, stirs 1h at a slow speed.Be cooled to 20～25 ℃ and stir 1h, 0～5 ℃ of stirring 1h, suction filtration is with 15ml * 2 purified water washing.Drain, vacuum-drying gets cefdinir 6.8g.Detect according to Chinese Pharmacopoeia (2010 editions), the result sees table 3:
Table 3
Can be found out that by table 3 data the cefdinir quality that the method for the invention obtains meets the requirement of Chinese Pharmacopoeia (2010 editions), content is more than 98%.
Claims (13)
1. the cefdinir ternary complex of formula II:
X=0.5 ~ 1 wherein, y=0.5 ~ 1.5.
2. the cefdinir ternary complex of formula II according to claim 1 is characterized in that, x=1, y=1.
3. the preparation method of the cefdinir ternary complex of the described formula II of claim 1 is characterized in that, is raw material with trityl cefdinir methylsulfonic acid DMAc mixture (V); In organic solvent; Earlier with phosphatase reaction, again with sulfuric acid reaction, or directly with phosphoric acid, vitriolic mixture reaction, or direct and formic acid, vitriolic mixture reaction; Or directly and acetate, vitriolic mixture reaction obtain
Wherein, Ph is a phenyl, and DMAc is a DMAC N,N, n=2 ~ 3.
4. preparation method according to claim 3 is characterized in that, said organic solvent is acetonitrile, ETHYLE ACETATE or methylene dichloride, and said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:5 ~ 15 with the weightmeasurement ratio of organic solvent.
5. preparation method according to claim 3 is characterized in that, said vitriolic mass concentration is 90 ~ 100%, and said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.2 ~ 0.5 with the vitriolic weight ratio.
6. preparation method according to claim 3 is characterized in that, the mass concentration of said phosphoric acid is 70 ~ 90%, and said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.5 ~ 1 with the weight ratio of phosphoric acid.
7. preparation method according to claim 3 is characterized in that, the mass concentration of said formic acid or acetate is 80 ~ 100%, and said trityl cefdinir methylsulfonic acid DMAc mixture (V) is 1:0.5 ~ 1.5 with the weight ratio of formic acid or acetate.
8. the preparation method of a cefdinir is a raw material with the cefdinir ternary complex of the described formula II of claim 1, adds purified water earlier and stirs, and adding alkali then, to regulate the pH value be 6 ~ 8, and adding acid for adjusting pH value is 1.5 ~ 3, and crystallization obtains cefdinir (I),
9. preparation method according to claim 8 is characterized in that, the weight ratio of said purified water and cefdinir ternary complex (II) is 5 ~ 30:1.
10. preparation method according to claim 8 is characterized in that, said alkali is two or more mixture of a kind of or arbitrary proportion in ammoniacal liquor, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium-acetate, the triethylamine.
11. preparation method according to claim 8 is characterized in that, saidly adds alkali to regulate the pH value be 6.8 ~ 7.5.
12. preparation method according to claim 8 is characterized in that, said acid is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetate.
13. preparation method according to claim 8 is characterized in that, the said acid for adjusting pH value that adds is 2.0 ~ 2.5.
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Cited By (2)
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| CN103012433A (en) * | 2012-12-13 | 2013-04-03 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefdinir crystal form B |
| CN106244660A (en) * | 2016-08-25 | 2016-12-21 | 艾美科健（中国）生物医药有限公司 | A kind of technique of enzymatic clarification cefdinir |
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| EP0304019A2 (en) * | 1987-08-19 | 1989-02-22 | Fujisawa Pharmaceutical Co., Ltd. | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) |
| WO2004016623A1 (en) * | 2002-08-13 | 2004-02-26 | Sandoz Ag | A cefdinir intermediate |
| CN1512996A (en) * | 2001-06-05 | 2004-07-14 | ����ҩƷ��ʽ���� | Crystalline acid salts of cefdinir and process for preparing cefdinir using same |
| CN1628118A (en) * | 2002-04-26 | 2005-06-15 | 兰贝克赛实验室有限公司 | Process for prepn. of cefdinir |
| KR20100122198A (en) * | 2009-05-12 | 2010-11-22 | 주식회사 하원제약 | Improved preparation method of cefdinir |
-
2012
- 2012-03-30 CN CN2012100884605A patent/CN102643293A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0304019A2 (en) * | 1987-08-19 | 1989-02-22 | Fujisawa Pharmaceutical Co., Ltd. | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) |
| CN1512996A (en) * | 2001-06-05 | 2004-07-14 | ����ҩƷ��ʽ���� | Crystalline acid salts of cefdinir and process for preparing cefdinir using same |
| CN1628118A (en) * | 2002-04-26 | 2005-06-15 | 兰贝克赛实验室有限公司 | Process for prepn. of cefdinir |
| WO2004016623A1 (en) * | 2002-08-13 | 2004-02-26 | Sandoz Ag | A cefdinir intermediate |
| KR20100122198A (en) * | 2009-05-12 | 2010-11-22 | 주식회사 하원제약 | Improved preparation method of cefdinir |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012433A (en) * | 2012-12-13 | 2013-04-03 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefdinir crystal form B |
| CN103012433B (en) * | 2012-12-13 | 2015-06-24 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefdinir crystal form B |
| CN106244660A (en) * | 2016-08-25 | 2016-12-21 | 艾美科健（中国）生物医药有限公司 | A kind of technique of enzymatic clarification cefdinir |
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