CN110452254A - The method for crystallising of Cloxacillin Sodium - Google Patents
The method for crystallising of Cloxacillin Sodium Download PDFInfo
- Publication number
- CN110452254A CN110452254A CN201910724200.4A CN201910724200A CN110452254A CN 110452254 A CN110452254 A CN 110452254A CN 201910724200 A CN201910724200 A CN 201910724200A CN 110452254 A CN110452254 A CN 110452254A
- Authority
- CN
- China
- Prior art keywords
- acetone
- added
- chloro
- phenyl
- crystallising
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/76—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with hetero rings directly attached to the carboxamido radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of method for crystallising of Cloxacillin Sodium, belong to technical field of medicine synthesis；Row acylation reaction is infiltrated by 6-amino-penicillanic acid, 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone, acetone is added after filtering, is crystallized；The acylation reaction: 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides is added in 6-amino-penicillanic acid under alkaline condition and acetone mixture carries out acylation reaction.The present invention has saved the use of solvent and auxiliary material in these above-mentioned steps, has reached save the cost without acidification, dehydration plus sodium iso-octoate crystallization, a step at salt purpose.Invention achieves a steps into the purpose of salt, shortens unnecessary process flow, improves yield, shortens the process time.
Description
Technical field
The present invention relates to a kind of method for crystallising of Cloxacillin Sodium, belong to technical field of medicine synthesis.
Background technique
Cloxacillin Sodium is a kind of semisynthetic penicillin product, extremely similar to oxacillin action character and purposes, right
The drug-resistant staphylococcus aureus product have bactericidal effect, are mainly used for infection caused by drug-resistant staphylococcus aureus, such as septicemia, osteomyelitis, soft group of skin
It is preferable to knit the curative effects such as infection, endocarditis, urinary system infection contamination and meningitis.Chemical name are as follows: 6- [3- (2- chlorphenyl) -5-
Methyl -4- isoxazole formamido] penicillanic acid sodium, molecular weight 475.87, chemical structural formula are as follows:
Summary of the invention
It is insufficient according to prior art, the technical problem to be solved by the present invention is providing a kind of crystallization of Cloxacillin Sodium
Method, crystallized without acidification, dehydration plus sodium iso-octoate and etc., save solvent and auxiliary material in these above-mentioned steps
Use, reached save the cost, a step at salt purpose.
The technical solution adopted by the present invention to solve the technical problems is: a kind of method for crystallising of Cloxacillin Sodium is provided,
Row acylation reaction is infiltrated by 6-amino-penicillanic acid, 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone, after filtering
Acetone is added, is crystallized；The acylation reaction: 3- Chloro-O-Phenyl -5- is added in 6-amino-penicillanic acid under alkaline condition
Methyl -4- isoxazole acyl chlorides and acetone mixture carry out acylation reaction.
The mass ratio of the 6-amino-penicillanic acid and 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides be 1:1.1~
1.2。
3- Chloro-O-Phenyl -5- methyl-in the 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone mixture
4- isoxazole acyl chlorides and acetone volume ratio are 1.0:5.0.
The alkaline condition pH is 10.0-11.0.
Passing through addition solid sodium bicarbonate adjustment pH after the completion of the acylation reaction is 10.0-11.0.
Acetone crystallization is added after the completion of the acylation reaction, the volumetric usage of acetone is 5 times of 6-amino-penicillanic acid.
Steps are as follows for the method for crystallising:
(1) 6-amino-penicillanic acid and 3- Chloro-O-Phenyl -5- methyl -4- isoxazole are weighed according to mass ratio 1:1.1~1.2
Acyl chlorides；
(2) acetone soln is measured according to 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone volume ratio 1.0:5.0；
(3) it takes dried and clean to obtain beaker first 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides is added, acetone is added afterwards
It makes it dissolve, it is stand-by to be prepared into solution A；
(4) purified water is measured according to the volume ratio 1:10.0~11.0 of 6-amino-penicillanic acid and water；
(5) accurate 6-amino-penicillanic acid will be weighed and measures the there-necked flask of accurate purified water addition dried and clean
In, sodium hydroxide solution is added dropwise to dissolved clarification, pH10.0~11.0 are controlled in course of dissolution, repetition measurement pH is unchanged after dissolved clarification；
(6) configured solution A is added in step (5), feed liquid becomes cloudy, and is stirred to react 20-30min；
(7) it is initially added into solid sodium bicarbonate after the reaction was completed, until keeping pH10.0~11.0 to feed liquid dissolved clarification；
(8) feed liquid after dissolved clarification in (7) step is filtered, is rejoined in the there-necked flask after cleaning, it is warming up to 13~
16 DEG C, the acetone of 5 times of the 6-amino-penicillanic acid volume amounts measured is added, is crystallized；
(9) stop being stirred to react after crystallization and stand growing the grain 120min.
(10) it is filtered after the completion of growing the grain, washed once with ethyl acetate, acetone washing is primary, with 30 after the completion of washing
DEG C~50 DEG C of forced air drying 8h obtain final products, Cloxacillin Sodium.
The method for crystallising of Cloxacillin Sodium of the present invention is by 6-amino-penicillanic acid and 3- Chloro-O-Phenyl -5- first
Base -4- isoxazole acyl chlorides carries out synthesis synthetic reaction under alkaline condition, first with sodium hydroxide solution by 6- amino before acylated
After penicillanic acid dissolved clarification, 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone mixture are added in system, carbon is used
Sour hydrogen sodium adjusts pH, and acetone is added in system and reaches a step into the process characteristic of salt.
The beneficial effects of the present invention are:
1, the present invention without acidification, dehydration, plus sodium iso-octoate crystallize and etc., saved in these above-mentioned steps
The use of solvent and auxiliary material, has reached save the cost, a step at salt purpose.
2, invention achieves a steps into the purpose of salt, shortens unnecessary process flow, improves yield, shortens
Process time.
Specific embodiment
The embodiment of the present invention is described further below:
Embodiment 1
At room temperature, it after 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides 22g being added in beaker, is added
110ml acetone soln is stirred dissolution with glass bar and solution A is made.
20g 6-amino-penicillanic acid is added in 41ml water at room temperature, stirring is opened and is adjusted to 100~120r/
Min is added dropwise sodium hydroxide solution and adjusts pH to 10.0~11.0, and dissolution is clarified, and repetition measurement pH is unchanged after dissolved clarification.
By configuration complete solution A be added in above-mentioned system, by be added solid sodium bicarbonate adjust pH10.0~
11.0, the 100ml acetone measured is added after solution dissolved clarification and carries out salt-forming reaction, stops stirring timing after crystal is precipitated and supports
Brilliant 120min；Then it is filtered, filter cake washed once with 110ml ethyl acetate and be filtered, and the filter cake after the completion of filtering is used
110ml acetone washing is once filtered again, and Cloxacillin Sodium powder crystallization is obtained after 30 DEG C of dryings of air blast.
Embodiment 2
At room temperature, it after 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides 23g being added in beaker, is added
110ml acetone soln is stirred dissolution with glass bar and solution A is made.
20g 6-amino-penicillanic acid is added in 41ml water at room temperature, stirring is opened and is adjusted to 100~120r/
Min is added dropwise sodium hydroxide solution and adjusts pH to 10.0~11.0, and dissolution is clarified, and repetition measurement pH is unchanged after dissolved clarification.
By configuration complete solution A be added in above-mentioned system, by be added solid sodium bicarbonate adjust pH10.0~
11.0, the 100ml acetone measured is added after solution dissolved clarification and carries out salt-forming reaction, stops stirring timing after crystal is precipitated and supports
Brilliant 120min；Then it is filtered, filter cake washed once with 110ml ethyl acetate and be filtered, and the filter cake after the completion of filtering is used
110ml acetone washing is once filtered again, and Cloxacillin Sodium powder crystallization is obtained after 40 DEG C of dryings of air blast.
Embodiment 3
At room temperature, it after 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides 24g being added in beaker, is added
110ml acetone soln is stirred dissolution with glass bar and solution A is made.
20g 6-amino-penicillanic acid is added in 41ml water at room temperature, stirring is opened and is adjusted to 100~120r/
Min is added dropwise sodium hydroxide solution and adjusts pH to 10.0~11.0, and dissolution is clarified, and repetition measurement pH is unchanged after dissolved clarification.
By configuration complete solution A be added in above-mentioned system, by be added solid sodium bicarbonate adjust pH10.0~
11.0, the 100ml acetone measured is added after solution dissolved clarification and carries out salt-forming reaction, stops stirring timing after crystal is precipitated and supports
Brilliant 120min；Then it is filtered, filter cake washed once with 110ml ethyl acetate and be filtered, and the filter cake after the completion of filtering is used
110ml acetone washing is once filtered again, and Cloxacillin Sodium powder crystallization is obtained after 50 DEG C of dryings of air blast.
Embodiment result
Claims (7)
1. a kind of method for crystallising of Cloxacillin Sodium, by 6-amino-penicillanic acid, 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl
Chlorine and acetone infiltrate row acylation reaction, and acetone is added after filtering, are crystallized；It is characterized in that the acylation reaction: 6-
3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides is added in aminopenicillanic acid under alkaline condition and acetone mixture carries out acyl
Change reaction.
2. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that the 6-amino-penicillanic acid
Mass ratio with 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides is 1:1.1~1.2.
3. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that the 3- Chloro-O-Phenyl -5- first
3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone volume ratio are 1.0 in base -4- isoxazole acyl chlorides and acetone mixture:
5.0。
4. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that the alkaline condition pH is
10.0-11.0。
5. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that after the completion of the acylation reaction
It is 10.0-11.0 by the way that solid sodium bicarbonate is added to adjust pH.
6. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that after the completion of the acylation reaction
Acetone crystallization is added, the volumetric usage of acetone is 5 times of 6-amino-penicillanic acid.
7. the method for crystallising of Cloxacillin Sodium according to claim 1, it is characterised in that steps are as follows for the method for crystallising:
(1) 6-amino-penicillanic acid and 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl are weighed according to mass ratio 1:1.1~1.2
Chlorine；
(2) acetone soln is measured according to 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides and acetone volume ratio 1.0:5.0；
(3) it takes dried and clean to obtain beaker first 3- Chloro-O-Phenyl -5- methyl -4- isoxazole acyl chlorides is added, the rear acetone that is added makes it
Dissolution, it is stand-by to be prepared into solution A；
(4) purified water is measured according to the volume ratio 1:10.0~11.0 of 6-amino-penicillanic acid and water；
(5) accurate 6-amino-penicillanic acid will be weighed and measure accurate purified water and be added in the there-necked flask of dried and clean, drop
Adding sodium hydroxide solution controls pH10.0~11.0 to dissolved clarification in course of dissolution, repetition measurement pH is unchanged after dissolved clarification；
(6) configured solution A is added in step (5), feed liquid becomes cloudy, and is stirred to react 20-30min；
(7) it is initially added into solid sodium bicarbonate after the reaction was completed, until keeping pH10.0~11.0 to feed liquid dissolved clarification；
(8) feed liquid after dissolved clarification in (7) step is filtered, rejoins in the there-necked flask after cleaning, is warming up to 13~16 DEG C,
The acetone of 5 times of the 6-amino-penicillanic acid volume amounts measured is added, is crystallized；
(9) stop being stirred to react after crystallization and stand growing the grain 120min.
(10) filtered after the completion of growing the grain, washed once with ethyl acetate, acetone washing is primary, after the completion of washing with 30 DEG C~
50 DEG C of forced air drying 8h obtain final products, Cloxacillin Sodium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910724200.4A CN110452254A (en) | 2019-08-07 | 2019-08-07 | The method for crystallising of Cloxacillin Sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910724200.4A CN110452254A (en) | 2019-08-07 | 2019-08-07 | The method for crystallising of Cloxacillin Sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110452254A true CN110452254A (en) | 2019-11-15 |
Family
ID=68485155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910724200.4A Pending CN110452254A (en) | 2019-08-07 | 2019-08-07 | The method for crystallising of Cloxacillin Sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110452254A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3278524A (en) * | 1962-03-13 | 1966-10-11 | Beecham Group Ltd | Penicillins and their production |
| RU2221801C1 (en) * | 2002-06-10 | 2004-01-20 | Савельев Евгений Александрович | Method of preparing 6-(3-phenyl-5-methylisoxazol-4- carbamino)penicillanic acid sodium salt |
| CN1613859A (en) * | 2004-08-11 | 2005-05-11 | 石药集团中诺药业（石家庄）有限公司 | Synthesis of austrastaph |
| CN102070653A (en) * | 2011-01-20 | 2011-05-25 | 河北华日药业有限公司 | Method for crystallizing cloxacillin sodium |
| CN102086213A (en) * | 2010-12-23 | 2011-06-08 | 天津大学 | Crystallization preparation method of cloxacillin sodium |
| RU2457221C2 (en) * | 2010-10-18 | 2012-07-27 | Валерий Александрович Шевцов | Composition for making articles for storing food products |
| CN105566349A (en) * | 2014-11-10 | 2016-05-11 | 青岛首泰农业科技有限公司 | Synthesis process of o-chloro-benzathine penicillin |
-
2019
- 2019-08-07 CN CN201910724200.4A patent/CN110452254A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3278524A (en) * | 1962-03-13 | 1966-10-11 | Beecham Group Ltd | Penicillins and their production |
| RU2221801C1 (en) * | 2002-06-10 | 2004-01-20 | Савельев Евгений Александрович | Method of preparing 6-(3-phenyl-5-methylisoxazol-4- carbamino)penicillanic acid sodium salt |
| CN1613859A (en) * | 2004-08-11 | 2005-05-11 | 石药集团中诺药业（石家庄）有限公司 | Synthesis of austrastaph |
| RU2457221C2 (en) * | 2010-10-18 | 2012-07-27 | Валерий Александрович Шевцов | Composition for making articles for storing food products |
| CN102086213A (en) * | 2010-12-23 | 2011-06-08 | 天津大学 | Crystallization preparation method of cloxacillin sodium |
| CN102070653A (en) * | 2011-01-20 | 2011-05-25 | 河北华日药业有限公司 | Method for crystallizing cloxacillin sodium |
| CN105566349A (en) * | 2014-11-10 | 2016-05-11 | 青岛首泰农业科技有限公司 | Synthesis process of o-chloro-benzathine penicillin |
Non-Patent Citations (2)
| Title |
|---|
| F. P. DOYL, ET AL.: "Derivatives of 6-aminopenicillanic acid. VI. Penicillins from 3- and 5-phenylisoxazole-4-carboxylic acids and their alkyl and halogen derivatives", 《JOURNAL OF THE CHEMICAL SOCIETY》 * |
| 李忠华: "氯唑西林钠的合成", 《山西大学学报（自然科学版）》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102898326B (en) | Preparation method of chlortetracycline hydrochloride | |
| CN103539803B (en) | A kind of method preparing ceftriaxone sodium | |
| CN100506210C (en) | Ceftezole sodium powder injection and synthesizing method thereof | |
| CN102268019B (en) | Cefadroxil compound and preparation method thereof | |
| CN101928292B (en) | Method for preparing cefuroxime acid | |
| CN101967156B (en) | Method for recrystallizing cefuroxime sodium | |
| CN103319502B (en) | Sulbenicillin sodium preparation method | |
| CN103467495A (en) | Method for preparing cefixime compound | |
| CN110452255A (en) | Crystal form of Ceftriaxone Sodium and preparation method thereof | |
| US8895728B2 (en) | Method for preparing cefmenoxime hydrochloride compound | |
| CN104844625A (en) | Cefamandole nafate new crystal form and crystallization preparing method thereof | |
| CN110452254A (en) | The method for crystallising of Cloxacillin Sodium | |
| CN101307060A (en) | Process for preparing hemihydrate of levofloxacin | |
| CN102559829A (en) | Synthetic method of ceftriaxone sodium crude salt | |
| CN106187921A (en) | A kind of preparation method of glipizide crystallization | |
| CN106565748A (en) | Preparation method for cefuroxime sodium and preparation thereof | |
| CN106749226A (en) | A kind of preparation method of avatrombopag maleates crystal formation C | |
| CN106478665A (en) | A kind of preparation technology of Cefradine crystallization | |
| CN102746323B (en) | Crystal form of cefuroxime acid and preparation method thereof | |
| CN109400491B (en) | Crystallization preparation method of L-p-hydroxyphenylglycine methyl ester | |
| CN104622695A (en) | Cefoxitin sodium powder preparation for injection | |
| CN108033971A (en) | A kind of synthetic method of Method of cefcapene pivoxil hydrochloride | |
| CN103724291A (en) | Synthetic method of pramipexole dihydrochloride related substance B | |
| CN106478669A (en) | A kind of process for purification of high-purity hydrochloric acid Ceftiofur | |
| CN102911186A (en) | Ceftizoxime sodium preparation and refining method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Applicant after: Ruiyang Pharmaceutical Co.,Ltd. Address before: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Applicant before: REYOUNG PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191115 |
|
| RJ01 | Rejection of invention patent application after publication |