CN1493574A - Production method of cefathiamidine-18 crystal - Google Patents
Production method of cefathiamidine-18 crystal Download PDFInfo
- Publication number
- CN1493574A CN1493574A CNA031296718A CN03129671A CN1493574A CN 1493574 A CN1493574 A CN 1493574A CN A031296718 A CNA031296718 A CN A031296718A CN 03129671 A CN03129671 A CN 03129671A CN 1493574 A CN1493574 A CN 1493574A
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- cephalosporin
- solvent
- mixed solvent
- alcohol
- filtration
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Abstract
A process for preparing the cephalosporin-18 crystal includes preparing the unsaturated solution of cephalosporin-18 in solvent, vacuum distilling to remove part of solvent and educing out cephalosporin-18, filtering, washing and drying.
Description
Technical field the present invention relates to water soluble antibiotics cephalosporin-18 crystalline manufacture method.
Technical background cephalosporin-the 18th, the first generation cephalosporin that China develops voluntarily is distributed widely in after the absorption in each organs and tissues, mainly through renal excretion.To G
+The effect of bacterium is better than G
-Bacterium, restraining effect to golden Portugal bacterium (comprising the penicillin Resistant strain), Streptococcus viridans, streptococcus pneumoniae etc. is stronger, faecalis there is bacteriostatic action preferably, is mainly used in golden Portugal bacterium (comprising the penicillin Resistant strain) clinically, the infection of streptococcus pneumoniae etc.Effect to urinary tract infections is also better.
Cephalosporin-18 also is cefathiamidine, pyrrole amidine cephalo, cefathiamidine.
Chemistry is by name: 7-(N, N '-diisopropyl amidino groups sulfur acetyl) Cephalosporanic acid inner salt.
Molecular structural formula is as follows:
At China's publication number is in the invention of application of CN1385434A, the crystallization method that discloses cephalosporin-18 is with single solvent or mixed solvent unsaturated solution to be made in cephalosporin-18 dissolving earlier, the solvent that in this unsaturated solution, adds the insoluble therein or indissoluble of a large amount of another kind of cephalosporins-18 then, thereby cephalosporin-18 solubleness in above mixed solvent is reduced, and then it is separated out from above mixed solvent.Get target product through crystallization, filtration, washing after drying.
In suitability for industrialized production; preparing of cephalosporin-18 crystalline product with the method fork-like farm tool used in ancient China of foregoing invention is that employed organic solvent amount is bigger than obvious defects; this will increase production cost of products undoubtedly, and labor safety and environment protection also are with the no small trouble of fork-like farm tool used in ancient China.
The crystallization of cephalosporin-18 is considered in our research of summary of the invention in the mode of reverse thinking: utilize the azeotropic principles of solvent or just carry out isolating principle according to solvent boiling point, select the suitable mixed solvent that contains methyl alcohol earlier cephalosporin-18 to be dissolved, remove methyl alcohol in the above mixed solvent with the spissated method of underpressure distillation then, thereby the solubleness of cephalosporin-18 in remaining solvent is reduced and separate out.
Be applied to the crystallization production of this product with method of the present invention, can reduce the consumption of solvent, thereby overcome quantity of solvent deficiency bigger than normal.
The present invention and publication number are that the essential distinction of invention of the application of CN1385434A is: make the solubleness of cephalosporin-18 reduce to separate out crystallization thereby the present invention is by being contained in the unsaturated solution that reduces cephalosporin-18 easy to be broad a dose; And thereby the method for CN1385434A is to make the solubleness of cephalosporin-18 reduce to separate out crystallization by adding indissoluble or insoluble solvent in the unsaturated solution of cephalosporin-18.
It is earlier cephalosporin-18 usefulness mixed solvent to be dissolved that the present invention utilizes the method for solvent azeotropic principles, at least contain the easily molten solvent of a kind of cephalosporin-18 and a kind of cephalosporin-18 indissoluble or insoluble solvent in this mixed solvent, and can form azeotropic in when distillation between easily molten solvent and indissoluble or the insoluble solvent, thereby when distillation, can take away the solvent of Yi Rong with a certain amount of indissoluble or insoluble solvent, the solubleness of cephalosporin-18 in residual solvent is reduced, and then separate out.
Azeotropic table composed as follows:
| Mixed solvent | Azeotropic is formed |
| Methanol/ethyl acetate | ????44％/56％ |
| Methyl alcohol/isopropyl acetate | ????80％/20％ |
It is earlier cephalosporin-18 usefulness mixed solvent to be dissolved that the present invention just carries out isolating principle according to solvent boiling point, at least contain the easily molten solvent of a kind of cephalosporin-18 and a kind of cephalosporin-18 indissoluble or insoluble solvent in this mixed solvent, and between easily molten solvent and indissoluble or the insoluble solvent evident difference is arranged on boiling point.Easily broad dose boiling point is lower than indissoluble or insoluble solvent, earlier lower boiling easy broad dose is removed when distillation, the solubleness of cephalosporin-18 in residual solvent is reduced, and then separate out.
Solvent boiling point such as following table:
| Organic solvent | Boiling point |
| Methyl alcohol | ????64.5℃ |
| Ethanol | ????78.3℃ |
| Virahol | ????82.4℃ |
| Dimethyl formamide | ????153℃ |
Easy to be broad dose of cephalosporin of the present invention-18 is methyl alcohol.
The indissoluble of cephalosporin of the present invention-18 or insoluble solvent are alcohol, acetic ester, the DMF of C2-C3.
The alcohol of C2-C3 of the present invention is preferentially selected ethanol, n-propyl alcohol, Virahol for use.
Acetic ester of the present invention is preferentially selected ethyl acetate, propyl acetate for use.
The DMF that the present invention relates to is a dimethyl formamide.
Embodiment
Embodiment one:
Under agitation, with the dissolving of 20 gram cephalosporin-18 usefulness, 300 ml methanol, the ethyl acetate that slowly adds 400 milliliters is made unsaturated solution, adds 0.5 gram activated carbon decolorizing, gets settled solution after the filtration.This solution concentrating under reduced pressure under 20 ℃ temperature is removed methyl alcohol, in solution, have more solid to separate out.Can add amount of ethyl acetate in case of necessity, remove methyl alcohol to steam as much as possible.At 6 hours after-filtration of 5 ℃ of following crystallizations, get 17.5 gram products with 50 milliliters ethyl acetate washing back drying under reduced pressure.
Embodiment two:
Under agitation,, slowly add 750 milliliters ethanol, make unsaturated solution, add 0.5 gram activated carbon decolorizing, get settled solution after the filtration the dissolving of 20 gram cephalosporin-18 usefulness, 250 ml methanol.This solution concentrating under reduced pressure under 20 ℃ temperature is removed methyl alcohol, steam as much as possible during operation, in solution, have more solid to separate out except that methyl alcohol.At 6 hours after-filtration of 5 ℃ of following crystallizations, get 16 gram products with drying under reduced pressure after 50 milliliters the washing with alcohol.
Embodiment three:
Under agitation, with the dissolving of 20 gram cephalosporin-18 usefulness, 300 ml methanol, the dimethyl formamide that slowly adds 300 milliliters is made unsaturated solution, adds 0.5 gram activated carbon decolorizing, gets settled solution after the filtration.This solution concentrating under reduced pressure under 20 ℃ temperature is removed methyl alcohol, in solution, have more solid to separate out.At 6 hours after-filtration of 5 ℃ of following crystallizations, get 15.5 gram products with 50 milliliters ethyl acetate washing back drying under reduced pressure.
Embodiment four:
Under agitation, with the dissolving of 20 gram cephalosporin-18 usefulness, 300 ml methanol, the Virahol that slowly adds 400 milliliters is made unsaturated solution, adds 0.5 gram activated carbon decolorizing, gets settled solution after the filtration.This solution concentrating under reduced pressure under 20 ℃ temperature is removed methyl alcohol, in solution, have more solid to separate out.At 6 hours after-filtration of 5 ℃ of following crystallizations, get 16.5 gram products with 50 milliliters ethyl acetate washing back drying under reduced pressure.
Claims (7)
1, the process for producing crystal of cephalosporin-18, it is characterized in that making the unsaturated solution of cephalosporin-18 with the mixed solvent that contains methyl alcohol, with activated carbon decolorizing, carry out concentrating under reduced pressure after the filtration to remove methyl alcohol wherein, cephalosporin-18 is separated out from remaining solvent, and crystallization, filtration, washing after drying get target compound.
2,, it is characterized in that also containing the alcohol of C2-C3 according to the mixed solvent of claim 1.
3,, it is characterized in that also containing acetic ester according to the mixed solvent of claim 1.
4,, it is characterized in that also containing DMF according to the mixed solvent of claim 1.
5, the alcohol according to the C2-C3 of claim 2 is ethanol, n-propyl alcohol, Virahol.
6, the acetic ester according to claim 3 is ethyl acetate, propyl acetate.
7, the DMF according to claim 4 is a dimethyl formamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031296718A CN1493574A (en) | 2003-07-03 | 2003-07-03 | Production method of cefathiamidine-18 crystal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031296718A CN1493574A (en) | 2003-07-03 | 2003-07-03 | Production method of cefathiamidine-18 crystal |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1493574A true CN1493574A (en) | 2004-05-05 |
Family
ID=34239754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031296718A Pending CN1493574A (en) | 2003-07-03 | 2003-07-03 | Production method of cefathiamidine-18 crystal |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1493574A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN104530083A (en) * | 2014-12-31 | 2015-04-22 | 天津大学 | New form crystal of cefathiamidine compound and preparation method of new crystal-form crystal |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
-
2003
- 2003-07-03 CN CNA031296718A patent/CN1493574A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN103012434B (en) * | 2012-12-14 | 2014-11-05 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN104530083A (en) * | 2014-12-31 | 2015-04-22 | 天津大学 | New form crystal of cefathiamidine compound and preparation method of new crystal-form crystal |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
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