CN102070653A - Method for crystallizing cloxacillin sodium - Google Patents
Method for crystallizing cloxacillin sodium Download PDFInfo
- Publication number
- CN102070653A CN102070653A CN2011100224812A CN201110022481A CN102070653A CN 102070653 A CN102070653 A CN 102070653A CN 2011100224812 A CN2011100224812 A CN 2011100224812A CN 201110022481 A CN201110022481 A CN 201110022481A CN 102070653 A CN102070653 A CN 102070653A
- Authority
- CN
- China
- Prior art keywords
- solution
- sodium
- acetone
- methyl
- chloro
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a method for crystallizing cloxacillin sodium, which comprises the following steps: weighing 6-aminopenicillanic acid and 3-chloro-O-phenyl-5-methyl-4-isoxazole acyl chloride according to a mass ratio of 1.0/0.5 to 2.5; adding water and acetone into the 6-aminopenicillanic acid to prepare a solution A; adding the 3-chloro-O-phenyl-5-methyl-4-isoxazole acyl chloride into the acetone to prepare a solution B; adding the solution B into the solution A to be uniformly stirred for carrying out acidylation reaction for 0.5 to 4h; adding acid for acidification after the reaction is completed, and adding mixed liquid of lower alcohol and butyl acetate for extraction; adding sodium iso-octoate organic solution for carrying out salt forming reaction, and carrying out reduced pressure distillation and crystal growing; and carrying out suction filtration, washing and drying. In the method provided by the invention, the product quality and the yield of the cloxacillin sodium can be effectively improved, the production period is shortened, and the production cost is reduced.
Description
Technical field
The present invention relates to the preparation method of compound, specifically the crystallization method of cloxacillin sodium.
Background technology
Cloxacillin sodium (Cloxacillin Sodium) is the wide spectrum semisynthetic penicillin, is applicable to respiratory tract infection due to the sensitive organism, gastrointestinal tract infection, urinary tract infections, soft tissue infection, endocarditis, meningitis, septicemia etc.Also can be used for the polyinfection due to micrococcus scarlatinae or streptococcus pneumoniae and the penicillin resistant staphylococcus.The chemistry of cloxacillin sodium by name (2S, 5R, 6R)-3, different mouthful of oxazole formamido group of 3-dimethyl-6-[5-methyl-3-(2-chloro-phenyl-)-4-]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt, molecular weight is 475.87, molecular formula: C
19H
17ClN
3NaO
5SH
2O, chemical structural formula is:
The preparation method of cloxacillin sodium is generally 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides (being called for short the adjacent chlorine of acyl chlorides), 6-amino-penicillanic acid (6-APA) respectively with mixing behind the acetone solution; carry out acylation reaction; acidifying after reaction finishes; extract with N-BUTYL ACETATE; obtain cloxacillin acid butyl ester solution; add the N-BUTYL ACETATE solution that contains Sodium isooctanoate again, reaction generates the cloxacillin sodium crystallization, carries out vacuum-drying after the crystallizing and washing.Because crystallization reaction can be subjected to all multifactor influences such as speed of response, velocity of diffusion, velocity of diffusion, particle arrangement speed and reaction heat, heat of phase transformation, therefore, existing method exists that liquid content is low, filtration time is long, be difficult for drying, crystal is little and imperfect, and crystal size is inhomogeneous, differences between batches are big, yield is low, and visible foreign matters is defective, shortcomings such as residual solvent is higher, production cost height.
Summary of the invention
Purpose of the present invention is exactly the crystallization method that a kind of new cloxacillin sodium will be provided, and in the hope of effectively improving the quality product and the yield of cloxacillin sodium, shortens the production cycle, reduces production costs.
The object of the present invention is achieved like this:
The crystallization method of cloxacillin sodium provided by the present invention may further comprise the steps:
A) be 1.0: 0.5～2.5 according to mass ratio, take by weighing 6-amino-penicillanic acid, 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides;
B) mass volume ratio according to 6-amino-penicillanic acid, water, acetone is 1.0: 5.0～50.0: 5～50.0, adds entry at 6-amino-penicillanic acid, and the ice bath cooling is regulated pH to 5.0～9.0 with alkali, adds acetone then and makes solution A;
C) mass volume ratio according to 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides, acetone is 1.0: 5.0～50.0, and 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is added in the acetone, and regulator solution pH value is 5.0-9.0, makes solution B;
D) solution B adds in the solution A, stirs, and carries out acylation reaction 0.5-4h;
E) after reaction finishes, be acidified with acid, terminal point control PH to 1.0-4.0, the mixed solution that adds mass ratio and be 1: 1～9 lower alcohol and butylacetate extracts;
F) in the extraction liquid of e step, add Sodium isooctanoate organic solution and be carried out to reactant salt, wherein the consumption of Sodium isooctanoate is 1: 0.5～2.0 in the mol ratio of 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides and Sodium isooctanoate; When the cloxacillin sodium content that is generated reaches for 5-25% (mg/ml), carry out underpressure distillation, after crystal is separated out, carry out growing the grain;
G) carry out suction filtration, washing then, vacuumize drying.
Extraction solvent is selected in the inventive method e step: mass ratio is 1: 1～9 the lower alcohol and the mixed solution of butylacetate, and rearing crystal time preferably was controlled at 5-60 minute, and it is bigger to form crystal thus, the cloxacillin sodium crystallization that crystal formation is more complete.
When the present invention carried out underpressure distillation in the f step, its negative pressure preferably was controlled at-0.070Mpa-0.098Mpa, can further improve cloxacillin sodium crystalline yield thus.
The inventive method is at 6-amino-penicillanic acid, add in the reaction process of 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides the methyl alcohol of specified proportion and the mixed solution of butylacetate are arranged, make thus the cloxacillin acid generated with Sodium isooctanoate organic solution when being carried out to reactant salt, directly do not separate out crystallization, and come the crystallization control process by underpressure distillation gradually, make crystal separate out gradually, pass through growing the grain again, improve the crystal formation of product, the cloxacillin sodium crystal that has overcome prior art for preparing is thin, difficult filtering defective, eliminating simultaneously has visible foreign matters in the crystal, solved problems such as residual solvent is defective.
The inventive method technology is handling good, with short production cycle, and batch difference is little, and prepared product crystal granularity has been increased to about 100 μ m by existing 30 μ m, and yield has improved 5.0-8.0%, and prepared crystal size uniformity.
The prepared cloxacillin sodium pH scope of the inventive method is 5.5～5.9 (fluctuation range is very little), and average content is 94.4% (CHP calculates content and is 〉=90.0% in cloxacillin acid standard), and specific rotation and residual solvent all meet the pharmacopeia requirement.
The contriver simultaneously in 20 batches test agent carried out the research (comprising influence factor test, accelerated test and test of long duration) of stability test, test shows, the cloxacillin sodium steady quality of the inventive method preparation.
Embodiment
Following examples are used for that the present invention is described in further detail, but with this protection scope of the present invention are not limited.
Embodiment 1
At room temperature, 10g 6-APA is added in the 40ml water, the ice bath cooling is regulated pH to 5.0-9.0 with ammoniacal liquor, adds 20ml acetone and makes solution A;
11g 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is added in the 60ml acetone, and regulator solution pH value be 6.0-8.0 that the unlatching stirring also is adjusted to 150r/min, makes solution B.
The 60ml solution B is added in the solution A, stir, adding by mass ratio is the mixed solution that 1: 1 methyl alcohol and butylacetate are formed; Add mass volume ratio concentration and be 10% Sodium isooctanoate DMF (dimethyl formamide) solution 100ml and be carried out to reactant salt, when the cloxacillin sodium content that is generated reaches 10% (mg/ml), carry out underpressure distillation, evacuated pressure is-0.07～-0.09Mpa, after crystal is separated out, carried out growing the grain 60 minutes; Carry out suction filtration, filter cake then with 100ml washing with acetone twice, vacuumize 50 ℃ and be drying to obtain white powder crystallization (being the cloxacillin sodium crystallization).Yield is 89.95%, crystal grain 100 μ m, and pH is 5.5, content is 94.2%, ultimate analysis, C
19H
17ClN
3NaO
5SH
2O, measured value (%): C, 47.65; H, 4.02; Cl, 7.6; N, 8.6; S, 6.75; Na, 5.1; H
2O, 3.81; Theoretical value: C, 47.95; H, 4.0; Cl, 7.45; N, 8.85; S, 6.75; Na, 4.85; H
2O, 4.0.
Embodiment 2
At room temperature, 10g 6-APA is added in the 100ml water, the ice bath cooling is regulated pH to 5.0-9.0 with sodium hydroxide solution, adds 100ml acetone and makes solution A;
15g 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is added in the 100ml acetone, and regulator solution pH value be 6.0-8.0 that the unlatching stirring also is adjusted to 50r/min, regulator solution pH value is 6.8-7.2, makes solution B;
Solution B is added in the solution A, stir, adding mass ratio is 1: 3 the ethanol and the mixed solution of butylacetate; Add mass volume ratio concentration and be the N-BUTYL ACETATE solution 60ml of 30% Sodium isooctanoate, be carried out to reactant salt, when the cloxacillin sodium content that is generated reaches 20% (mg/ml), carry out underpressure distillation gradually, evacuated pressure is-0.07～-0.09Mpa, after crystal is separated out, carried out growing the grain 90 minutes; Carry out suction filtration, filter cake then with 100ml washing with acetone twice, vacuumize 50 ℃ and be drying to obtain white powder crystallization (being the cloxacillin sodium crystallization).Yield is 93.25%, crystal grain 100 μ m, and pH is 5.6, content is 95.1%, ultimate analysis, C
19H
17ClN
3NaO
5SH
2O, measured value (%): C, 47.65; H, 4.02; Cl, 7.6; N, 8.6; S, 6.75; Na, 5.1; H
2O, 3.81; Theoretical value: C, 47.95; H, 4.0; Cl, 7.45; N, 8.85; S, 6.75; Na, 4.85; H
2O, 4.0.
Embodiment 3
At room temperature, 10g 6-APA is added in the 75ml water, the ice bath cooling is regulated pH to 5.0-9.0 with ammoniacal liquor, adds 150ml acetone and makes solution A;
16g 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is added in the 150ml acetone, and regulator solution pH value be 6.0-8.0 that the unlatching stirring also is adjusted to 50r/min, makes solution B;
Solution B is added in the solution A, stir, adding mass ratio is 1: 9 the Virahol and the mixed solution of butylacetate; Adding mass volume ratio concentration is 50% Sodium isooctanoate methyl iso-butyl ketone (MIBK) (MIBK) solution 60ml, be carried out to reactant salt, when the cloxacillin sodium content that is generated reaches 20% (mg/ml), carry out underpressure distillation gradually, evacuated pressure is-0.07～-0.09Mpa, after crystal is separated out, carried out growing the grain 120 minutes; Carry out suction filtration, filter cake then with 150ml washing with acetone twice, vacuumize 50 ℃ and be drying to obtain white powder crystallization (being the cloxacillin sodium crystallization).Yield is 91.38%, crystal grain 90 μ m, and pH is 5.6, content is 94.2%, ultimate analysis, C
19H
17ClN
3NaO
5SH
2O, measured value (%): C, 47.65; H, 4.02; Cl, 7.6; N, 8.6; S, 6.75; Na, 5.1; H
2O, 3.81; Theoretical value: C, 47.95; H, 4.0; Cl, 7.45; N, 8.85; S, 6.75; Na, 4.85; H
2O, 4.0.
The comparative example
13.2g 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is dissolved 6-amino-penicillanic acid (6-APA) with acetone 10ml
10g is suspended among the water 300ml, and is molten clear with sodium hydroxide, adds acetone solution reaction 60min, extract sulfuric acid acidation, the N-BUTYL ACETATE liquid of adding Sodium isooctanoate 7.7g with N-BUTYL ACETATE, promptly separate out the cloxacillin sodium crystallization, the 2h after-filtration carries out vacuum-drying after washing twice.Yield is 75.38%, crystal grain 30 μ m, and pH is 5.2, content is 90.2%, ultimate analysis, C
19H
17ClN
3NaO
5SH
2O, measured value (%): C, 47.65; H, 4.02; Cl, 7.6; N, 8.6; S, 6.75; Na, 5.1; H
2O, 3.81; Theoretical value: C, 47.95; H, 4.0; Cl, 7.45; N, 8.85; S, 6.75; Na, 4.85; H
2O, 4.0.
Claims (3)
1. the crystallization method of a cloxacillin sodium is characterized in that it may further comprise the steps:
(a) be 1.0: 0.5～2.5 according to mass ratio, take by weighing 6-amino-penicillanic acid, 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides;
(b) mass volume ratio according to 6-amino-penicillanic acid, water, acetone is 1.0: 5.0～50.0: 5～50.0, adds entry at 6-amino-penicillanic acid, and the ice bath cooling is regulated pH to 5.0～9.0 with alkali, adds acetone then and makes solution A;
(c) mass volume ratio according to 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides, acetone is 1.0: 5.0～50.0, and 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides is added in the acetone, and regulator solution pH value is 5.0-9.0, makes solution B;
(d) solution B adds in the solution A, stirs, and carries out acylation reaction 0.5-4h;
(e) after reaction finishes, be acidified with acid, terminal point control PH to 1.0-4.0, the mixed solution that adds mass ratio and be 1: 1～9 lower alcohol and butylacetate extracts;
(f) in the extraction liquid of e step, add Sodium isooctanoate organic solution and be carried out to reactant salt, wherein the consumption of Sodium isooctanoate is in 3-Chloro-O-Phenyl-5-methyl-4-isoxazole acyl chlorides: the mol ratio of Sodium isooctanoate is 1: 0.5～2.0; When the cloxacillin sodium content that is generated reaches for 5-25% (mg/ml), carry out underpressure distillation, after crystal is separated out, carry out growing the grain;
(g) carry out suction filtration, washing then, vacuumize drying.
2. the crystallization method of cloxacillin sodium according to claim 1 is characterized in that adopting in the vacuum distillation process in the f step, and the negative pressure of underpressure distillation is controlled at-0.070Mpa-0.098Mpa.
3. the crystallization method of cloxacillin sodium according to claim 1 and 2 is characterized in that extraction solvent is selected in the e step: mass ratio is 1: 1～9 the lower alcohol and the mixed solution of butylacetate, and rearing crystal time was controlled at 5-60 minute.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100224812A CN102070653A (en) | 2011-01-20 | 2011-01-20 | Method for crystallizing cloxacillin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100224812A CN102070653A (en) | 2011-01-20 | 2011-01-20 | Method for crystallizing cloxacillin sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102070653A true CN102070653A (en) | 2011-05-25 |
Family
ID=44029431
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100224812A Pending CN102070653A (en) | 2011-01-20 | 2011-01-20 | Method for crystallizing cloxacillin sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102070653A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452254A (en) * | 2019-08-07 | 2019-11-15 | 瑞阳制药有限公司 | The method for crystallising of Cloxacillin Sodium |
| CN111205305A (en) * | 2020-02-07 | 2020-05-29 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2201419C2 (en) * | 2001-05-04 | 2003-03-27 | Савельев Евгений Александрович | Method of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamino]-penicillanic acid sodium salt preparing |
-
2011
- 2011-01-20 CN CN2011100224812A patent/CN102070653A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2201419C2 (en) * | 2001-05-04 | 2003-03-27 | Савельев Евгений Александрович | Method of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamino]-penicillanic acid sodium salt preparing |
Non-Patent Citations (3)
| Title |
|---|
| 《山西大学学报（自然科学版）》 20021231 李忠华 氯唑西林钠的合成 224-226 1-3 第25卷, 第3期 * |
| 《有机药物合成手册》 19761231 上海医药工业研究院技术情报站 合成及半合成抗生素 112-115 1-3 , * |
| 李忠华: "氯唑西林钠的合成", 《山西大学学报（自然科学版）》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452254A (en) * | 2019-08-07 | 2019-11-15 | 瑞阳制药有限公司 | The method for crystallising of Cloxacillin Sodium |
| CN111205305A (en) * | 2020-02-07 | 2020-05-29 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
| CN111205305B (en) * | 2020-02-07 | 2021-10-22 | 山东二叶制药有限公司 | Preparation process of cloxacillin sodium |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102321101B (en) | Preparation method of cefazolin sodium | |
| CN104327100B (en) | High-purity 6315-S preparation technology | |
| CN105541870A (en) | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium | |
| CN104771372A (en) | Cefuroxime sodium powder preparation for injection | |
| CN102161667B (en) | Sulbenicillin sodium and sulbenicillin sodium used for injection | |
| CN105503904A (en) | Preparation method for cefotaxime acid | |
| CN102070653A (en) | Method for crystallizing cloxacillin sodium | |
| CN102134250A (en) | Crystallization method of cefadroxil monohydrate and crystals | |
| CN102702227A (en) | Preparation method for flucloxacillin sodium | |
| CN101585845B (en) | Preparation process of Mezlocillin | |
| US9409940B2 (en) | Preparation process of erythromycin thiocyanate | |
| CN106565748A (en) | Preparation method for cefuroxime sodium and preparation thereof | |
| CN103012437A (en) | Method for preparing cefoxitin acid as antibacterial medicament | |
| CN106317080A (en) | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof | |
| CN104230955B (en) | A kind of preparation method to the acid of hydroxyl penicillin V and salt thereof | |
| Tosoni et al. | Crystalline p-aminobenzylpenicillin: preparation and some properties | |
| CN1162434C (en) | Improved process for rifa high-density raw powder I type crystal | |
| CN112358489A (en) | Production method of industrial penicillin sulfoxide product | |
| CN102086213B (en) | Crystallization preparation method of cloxacillin sodium | |
| CN118580255A (en) | Crystallization method of cloxacillin sodium | |
| CN105218562A (en) | A kind of preparation method of D (-)-Sulfocillin | |
| CN105566349A (en) | Synthesis process of o-chloro-benzathine penicillin | |
| CN108659007B (en) | Preparation method of cylindrical dicloxacillin sodium crystal | |
| CN105343067B (en) | Amoxicillin sodium for injection potassium clavulanate preparation and preparation method thereof | |
| CN102690277B (en) | Preparation method of chlorazol benzathine benzylpenicillin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110525 |