DE3911321A1 - Process for the preparation of cefazolin sodium salt - Google Patents
Process for the preparation of cefazolin sodium saltInfo
- Publication number
- DE3911321A1 DE3911321A1 DE19893911321 DE3911321A DE3911321A1 DE 3911321 A1 DE3911321 A1 DE 3911321A1 DE 19893911321 DE19893911321 DE 19893911321 DE 3911321 A DE3911321 A DE 3911321A DE 3911321 A1 DE3911321 A1 DE 3911321A1
- Authority
- DE
- Germany
- Prior art keywords
- sodium
- cefazolin
- preparation
- sodium salt
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 6
- 229960001139 cefazolin Drugs 0.000 title claims abstract description 5
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 title claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 7
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 7
- 229960003408 cefazolin sodium Drugs 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
In DE-OS 27 52 443 ist die Herstellung von kristllinem Cefazolin-NatriumsalzDE-OS 27 52 443 is the production of crystalline Cefazolin sodium salt
beschrieben.described.
Nach diesem Verfahren wird Cefazolin-Natrium in einem Wasser-Ethanol-Gemisch bei -10 bis -30°C kristallisiert und anschließend gefriergetrocknet.According to this procedure, cefazolin sodium is combined in one Water-ethanol mixture crystallizes at -10 to -30 ° C and then freeze-dried.
Es wurde nun gefunden, daß das sehr gut wasserlösliche Cefazolin-Natrium (wäßrige Lösung = Applikationsform) wider Erwarten aus wäßriger Lösung durch Aufkonzentrieren in Form von Nadeln kristallisiert werden kann.It has now been found that the very water-soluble Cefazolin sodium (aqueous solution = application form) is reflected Expect from aqueous solution by concentrating in the form can be crystallized by needles.
Gegenstand der Erfindung ist somit ein Verfahren zur Herstellung von kristallinem Cefazolin-Natrium, das dadurch gekennzeichnet ist, daß man Cefazolin-Säure in Wasser mit einem Natriumspender in Lösung bringt und durch Aufkonzentrieren dieser Lösung kristallisiert.The invention thus relates to a method for Production of crystalline sodium cefazolin, thereby is characterized in that with cefazolinic acid in water a sodium donor in solution and through Concentrate this solution crystallized.
Als Natriumspender kommen z.B. Natriumhydroxid, Natriumacetat, Natriumbicarbonat, vorzugsweise Natrium-2- ethylhexanoat und Natriumhydroxid in Betracht. Das Natriumhydroxid kann beispielsweise in Form einer 1n-Lösung eingesetzt werden. As sodium donors e.g. Sodium hydroxide, Sodium acetate, sodium bicarbonate, preferably sodium 2 ethyl hexanoate and sodium hydroxide. The Sodium hydroxide can for example be in the form of a 1n solution be used.
Die Herstellung der Natriumsalz-Lösung erfolgt zweckmäßig bei Raumtemperatur. Anschließend wird im allgemeinen noch sterilfiltriert und dann aufkonzentriert.The sodium salt solution is expediently prepared at room temperature. Subsequently, in general sterile filtered and then concentrated.
Durch schonendes Aufkonzentrieren, möglichst im Vakuum, zweckmäßigerweise bei Temperaturen unter 60°C, bevorzugt zwischen 20 und 40°C, wird Cefazolin-Natrium schon bei Raumtemperatur oder auch bei tieferen Temperaturen um 0°C auskristallisiert.By gentle concentration, if possible in a vacuum, expediently at temperatures below 60 ° C., preferred between 20 and 40 ° C, cefazolin sodium is already at Room temperature or at lower temperatures around 0 ° C crystallized out.
Durch Zusatz von Alkoholen bei der Isolierung - bevorzugt wird Ethanol eingesetzt - zu der Cefazolin-Natriumsalz- Suspension, wird die Kristallisation vervollständigt, wobei auch eine schwache Kühlung beispielsweise auf etwa 0°C günstig sein kann. Die Kristallsuspension wird dann noch durch weitere Ethanolzugabe verdünnt, die Kristalle abgesaugt, mit Ethanol gewaschen und im Vakuum getrocknet.By adding alcohols during the isolation - ethanol is preferably used - to the cefazolin sodium salt suspension, the crystallization is completed, although weak cooling, for example to about 0 ° C., can also be favorable. The crystal suspension is then diluted by further ethanol addition, the crystals are suctioned off, washed with ethanol and dried in vacuo.
Die Kristallisation unter Aufkonzentrieren kann auch durch Azeotropdestillation erfolgen. Das Wasser wird dabei teilweise oder ganz mittels eines Schleppers, z.B. n-Butanol, unter vermindertem Druck beispielsweise bei Temperaturen um 40°C entfernt, wobei bereits die Auskristallisation erfolgt. Cafazolin-Natrium wird in diesem Fall beispielsweise aus Butanol oder Butanol-Wasser isoliert.The crystallization with concentration can also by Azeotropic distillation takes place. The water is there partially or entirely by means of a tractor, e.g. n-butanol, for example at reduced pressure Temperatures around 40 ° C away, where already the Crystallization takes place. Cafazolin sodium is used in this Case, for example, from butanol or butanol water isolated.
Es war nicht vorauszusehen, daß die im Vergleich zu DE-OS 27 52 443 wesentlich vereinfachten Maßnahmen, insbesondere auch im Hinblick auf die sehr gute Löslichkeit des Produktes zu einem gut kristallisierenden Natriumsalz führen würden.It was not foreseeable that the compared to DE-OS 27 52 443 significantly simplified measures, in particular also with regard to the very good solubility of the product would lead to a well crystallizing sodium salt.
25 g Cefazolin-Säure werden in 125 ml Wasser suspendiert und
durch Zugabe von 1 n Natronlauge ad pH 8,5 gelöst. Die
Lösung wird mit 0,5 g Aktivkohle geklärt, danach im Vakuum
bei F40°C Badtemperatur auf 30-40% des Anfangsvolumens
eingeengt, wobei Kristallisation eintritt. Die
Kristallsuspension wird mit 125 ml Ethanol versetzt, 1
Stunde bei Raumtemperatur gerührt und über Nacht bei 0°C
aufbewahrt. Die Kristalle werden abgesaugt, mit 50 ml
Ethanol gewaschen und bei Raumtemperatur im Vakuum
getrocknet.
Ausbeute: 22,83 g (80% d.Th.)
(Die Mutterlauge kann rezyklisiert werden bzw. durch
Ansäuern auf pH 1,9 kann Cefazolin-Säure zurückgewonnen
werden.)25 g of cefazolinic acid are suspended in 125 ml of water and dissolved by adding 1N sodium hydroxide solution to pH 8.5. The solution is clarified with 0.5 g of activated carbon, then concentrated in vacuo at a bath temperature of F40 ° C. to 30-40% of the initial volume, with crystallization occurring. 125 ml of ethanol are added to the crystal suspension, the mixture is stirred at room temperature for 1 hour and stored at 0 ° C. overnight. The crystals are filtered off, washed with 50 ml of ethanol and dried in vacuo at room temperature.
Yield: 22.83 g (80% of theory)
(The mother liquor can be recycled or cefazolinic acid can be recovered by acidification to pH 1.9.)
20 g Cefazolin-Säure werden in 125 ml Wasser suspendiert und
mit 1 n Natronlauge bei max. pH 8,5 gelöst. Man klärt mit
0,5 kg Aktivkohle und destilliert aus dem Filtrat nach
Zusatz von 250 ml n-Butanol, das bei Bedarf ergänzt wird,
das Wasser azeotrop im Vakuum ab, bis schließlich
Cefazolin-Natrium in kristalliner Form in Wasser/Butanol
oder Butanol vorliegt. Man kühlt auf Raumtemperatur ab,
saugt die Kristalle ab und wäscht sie mit 100 ml Ethanol.
Trocknung im Vakuum bei Raumtemperatur, im Stickstoffstrom.
Ausbeute: 24,9 g (95% d.Th.).20 g of cefazolinic acid are suspended in 125 ml of water and mixed with 1N sodium hydroxide solution at max. pH 8.5 dissolved. The mixture is clarified with 0.5 kg of activated carbon and the water is azeotropically distilled from the filtrate after addition of 250 ml of n-butanol, which can be added if necessary, until finally cefazolin sodium is present in crystalline form in water / butanol or butanol . The mixture is cooled to room temperature, the crystals are filtered off and washed with 100 ml of ethanol. Drying in vacuum at room temperature, in a stream of nitrogen.
Yield: 24.9 g (95% of theory).
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19893911321 DE3911321A1 (en) | 1989-04-07 | 1989-04-07 | Process for the preparation of cefazolin sodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19893911321 DE3911321A1 (en) | 1989-04-07 | 1989-04-07 | Process for the preparation of cefazolin sodium salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3911321A1 true DE3911321A1 (en) | 1990-10-11 |
Family
ID=6378102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19893911321 Withdrawn DE3911321A1 (en) | 1989-04-07 | 1989-04-07 | Process for the preparation of cefazolin sodium salt |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3911321A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2244716C1 (en) * | 2003-06-27 | 2005-01-20 | Савельев Евгений Александрович | Method for preparing 7-(1h-tetrazol-1-yl)-acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl)-3-cephem-4-carboxylic acid sodium salt (cefazolin) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1953861A1 (en) * | 1969-10-25 | 1971-05-06 | Fujisawa Pharmaceutical Co | Antibacterial cephalosporin compsns |
| DE2752443A1 (en) * | 1976-11-24 | 1978-06-01 | Lilly Co Eli | PROCESS FOR PRODUCING CEPHAZOLINE SODIUM |
| EP0060301A1 (en) * | 1980-09-19 | 1982-09-22 | Asahi Kasei Kogyo Kabushiki Kaisha | Process for preparing cephalosporin compounds |
| EP0327081A2 (en) * | 1988-02-05 | 1989-08-09 | Fujisawa Pharmaceutical Co., Ltd. | Alpha-crystals of cefazolin sodium |
-
1989
- 1989-04-07 DE DE19893911321 patent/DE3911321A1/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1953861A1 (en) * | 1969-10-25 | 1971-05-06 | Fujisawa Pharmaceutical Co | Antibacterial cephalosporin compsns |
| DE2752443A1 (en) * | 1976-11-24 | 1978-06-01 | Lilly Co Eli | PROCESS FOR PRODUCING CEPHAZOLINE SODIUM |
| EP0060301A1 (en) * | 1980-09-19 | 1982-09-22 | Asahi Kasei Kogyo Kabushiki Kaisha | Process for preparing cephalosporin compounds |
| EP0327081A2 (en) * | 1988-02-05 | 1989-08-09 | Fujisawa Pharmaceutical Co., Ltd. | Alpha-crystals of cefazolin sodium |
Non-Patent Citations (1)
| Title |
|---|
| J. Antibiotics 23(1970)131-136 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2244716C1 (en) * | 2003-06-27 | 2005-01-20 | Савельев Евгений Александрович | Method for preparing 7-(1h-tetrazol-1-yl)-acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl)-3-cephem-4-carboxylic acid sodium salt (cefazolin) |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| 8130 | Withdrawal |