CN102617607A - Method for preparing cefazolin compounds - Google Patents
Method for preparing cefazolin compounds Download PDFInfo
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- CN102617607A CN102617607A CN2012100930069A CN201210093006A CN102617607A CN 102617607 A CN102617607 A CN 102617607A CN 2012100930069 A CN2012100930069 A CN 2012100930069A CN 201210093006 A CN201210093006 A CN 201210093006A CN 102617607 A CN102617607 A CN 102617607A
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Abstract
The invention belongs to the field of pharmacy and relates to a method for preparing cefazolin compounds. The method comprises the following steps that: 1, cefazolin sodium imidazo (toluene diamine TDA) is synthetized, thiadiazole and 7-ACA are obtained through reaction, dimethyl carbonate is used as solvents in the reaction, boron trifluoride-dimethyl carbonate is used as catalysts, and reagents used for regulating the pH of the reaction liquid are inorganic alkali after the reaction is completed; 2, anhydride is prepared, and the anhydride is obtained through the reaction between tetrazole acetic acid and pivaloyl chloride, and 3, the cefazolin is synthesized, TDA solution reacts with the anhydride, and the reaction solution is subjected to decoloration and purification through an aluminium oxide column.
Description
Technical field:
The present invention relates to a kind of preparation method of antimicrobial compounds, particularly a kind of preparation method of Kefzol compound.
Background technology:
Kefzol, chemical name be (6R, 7R)-3-[(5-methyl isophthalic acid; 3; 4-thiadiazoles-2-yl) thiomethyl]-8-oxo-7-[[2-(tetrazolium-1-yl) acetyl] amino]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, Kefzol is the semi-synthetic cynnematin of the first-generation, antimicrobial spectrum is identical with Cephalexin Monohydrate Micro/Compacted; But act on byer force, its Plasma Concentration is higher under Isodose.The characteristics of these article are stronger to the effect of gram-negative bacteria, have advantage acidproof, efficient, low toxicity.Clinical respiratory tract, urethra, pneumonia, cholecystitis, liver abscess, peritonitis, pelvic inflammatory disease, endocarditis, otitis media, septicemia and the soft tissue infection etc. that are applicable to due to the sensitive organism.
The preparation method of relevant Kefzol has many, like Chinese patent:
A kind of preparation method of cephazolin sodium, application number: 201110214214
A kind of 2-methyl-5-sulfydryl-1,3, the compound method of 4-thiadiazoles, application number: 201110218412
A kind of cefazolin sodium pentahydrate compound of variation route, application number: 200910169646
Three intermediates preparation of Kefzol, application number: 200410043639
The preparation method of Kefzol, application number: 00121531
The method for preparing Kefzol, application number: 96117398
But method of the prior art, use has certain toxic organic solvent and reagent more, deals with the comparison difficulty; Environment there is certain pollution, in addition, for obtaining the decontamination simultaneously of the high route of high product of purity and yield; Need in building-up process, use suitable solvent and reagent; The present invention has found a kind of compound method through screening, has solved the problems referred to above.
Summary of the invention:
The invention discloses a kind of preparation method who prepares the Kefzol compound.Preparing method of the present invention may further comprise the steps:
Synthesizing of step 1, three midbodys of sodium CEZ (TDA), thiadiazoles and 7-ACA reaction obtain, and reaction is a solvent with the methylcarbonate, and boron trifluoride-methylcarbonate is a catalyzer, transfers the solution iso-electric point with yellow soda ash;
The preparation of step 2, acid anhydrides, tetrazoleacetic acid and pivaloyl chloride reaction obtain acid anhydrides;
Synthesizing of step 3, Cephazolin, TDA solution and anhydride reaction, reaction soln is purified through the decolouring of aluminium sesquioxide pillar.
Wherein, solvent for use is a methylcarbonate in the step 1; After reaction finished, transferring reaction solution PH agents useful for same was mineral alkali, the yellow soda ash of preferred environmental protection, boron trifluoride and 7-ACA weight ratio scope 0.7-1.3.
In the step 3, need dripping hydrochloric acid to PH1.3-1.6, preferred 1.5, during the Kefzol acid crystal, the disperse phase of employing is ETHYLE ACETATE and alcoholic acid mixed solvent, and ETHYLE ACETATE and ethanol mixed solvent weight ratio scope are 0.5-1.5.
The more original compared with techniques contrast of novel method is (contrast of Kefzol index) as follows
| Batch | Content | Yield (always) | The look level |
| 1 (old) | 97.2％ | 108％ | 3 |
| 2 (old) | 96.5％ | 109.5％ | 3 |
| 3 (old) | 98％ | 110％ | 4 |
| 4 (newly) | 98.8％ | 119.5％ | 1 |
| 5 (newly) | 99.0％ | 119％ | 1 |
| 6 (newly) | 99.1％ | 118.8％ | 1 |
Advantage of the present invention:
1, the solvent methylcarbonate of this process using is the environmental protection solvent.And it is simple that solvent reclaims technology, and the recovery is high.Boron trifluoride and 7-ACA weight ratio scope 0.7-1.3.
2, in the TDA crystallisation process, adopt the yellow soda ash of environmental protection to transfer the solution iso-electric point.
3, in the Cephazolin acid building-up process, water adopts the aluminium sesquioxide pillar to purify, and has improved the quality of product.
4, the Kefzol acid crystal time, the disperse phase of employing is ETHYLE ACETATE and alcoholic acid mixed solvent, has improved the crystalline form of product, improves the quality of product simultaneously again, and ETHYLE ACETATE and ethanol mixed solvent weight ratio scope are 0.5-1.5.
Method of the present invention significantly improves the existing compound method of quality product.This method operation steps is short, and yield is high, and cost is low, is fit to industrialized production.
Embodiment:
Below, further specify the present invention through embodiment, but not as limitation of the present invention.
Embodiment 1
Three midbodys of step 1 sodium CEZ (TDA) are synthetic,
In the condensation jar, add the 50g methylcarbonate, 69g boron trifluoride-methylcarbonate is opened stirring, in jar, drops into thiadiazoles 13g, and 7-ACA25g heats up simultaneously, and 30～40 ℃ of temperature of reaction are reacted residual less than 1.0% to 7-ACA.After having reacted, be cooled to below 10 degree, reaction solution moved into be equipped with in the there-necked flask of 300ml deionized water, drip sodium carbonate solution, be cooled to 10 ℃, stirred growing the grain 1 hour to pH2～4.Filter, use the washing with acetone after drying.
The preparation of step 2 acid anhydrides
Methylene dichloride 150ml adds tetrazoleacetic acid 8.9g, cools to-50 ± 1 ℃; In 15 minutes, dripping triethylamine is stirred to tetrazoleacetic acid and all dissolves; Holding temperature-55 ± 1 ℃ drips pivaloyl chloride 8g, and reaction obtained the acid anhydrides solution for standby after 60 minutes under holding temperature-30 ± 1 ℃ temperature.
The acid of step 3 Cephazolin is synthetic
To methylene dichloride 180ml, add TDA23g, be cooled to-30 ± 2 ℃, in 30 minutes, drip tetramethyl guanidine then and all dissolve to TDA.Join TDA solution in the acid anhydrides solution reactor, controlled temperature-30 ± 1 ℃ reaction 1 hour adds water 300ml, transfers PH5～7 with triethylamine; Stir 15 minutes static layering, methylene dichloride addition entry 70ml transfers PH5～7 with triethylamine, static phase-splitting; Merge water, add gac 2g decolouring, stir 20 minutes filtration washing backs and merge water; Water is through the decolouring of aluminium sesquioxide pillar, and behind the collection water, adding weight ratio is ETHYLE ACETATE and the alcoholic acid mixed solvent 80ml of 0.5-1.5; Dripping hydrochloric acid is lowered the temperature 10～15 ℃ to PH1.3-1.6,1 hour after-filtration drying of growing the grain.
Claims (5)
1. the preparation method of a Kefzol may further comprise the steps:
Synthesizing of step 1, three midbodys of sodium CEZ (TDA), thiadiazoles and 7-ACA reaction obtain, and reaction is a solvent with the methylcarbonate, and boron trifluoride-methylcarbonate is a catalyzer, and after reaction finished, accent reaction solution PH agents useful for same was a mineral alkali;
The preparation of step 2, acid anhydrides, tetrazoleacetic acid and pivaloyl chloride reaction obtain acid anhydrides;
Synthesizing of step 3, Cephazolin, TDA solution and anhydride reaction, reaction soln is purified through the decolouring of aluminium sesquioxide pillar.
2. according to the preparation method of claim 1, it is characterized in that wherein, solvent for use is a methylcarbonate in the step 1; After reaction finished, transferring reaction solution PH agents useful for same was yellow soda ash, boron trifluoride and 7-ACA weight ratio scope 0.7-1.3.
3. according to the preparation method of claim 1, it is characterized in that, wherein; In the step 3, need dripping hydrochloric acid, during the Kefzol acid crystal to PH1.3-1.6; The disperse phase that adopts is ETHYLE ACETATE and alcoholic acid mixed solvent, and ETHYLE ACETATE and ethanol mixed solvent weight ratio scope are 0.5-1.5.
4. according to the preparation method of claim 1, it is characterized in that, wherein, in the step 3, need dripping hydrochloric acid to PH1.5.
5. according to the preparation method of claim 1, it is characterized in that step is following:
Three midbodys of step 1 sodium CEZ (TDA) are synthetic,
In the condensation jar, add the 50g methylcarbonate, 69g boron trifluoride-methylcarbonate is opened stirring, in jar, drops into thiadiazoles 13g, and 7-ACA25g heats up simultaneously, and 30～40 ℃ of temperature of reaction are reacted residual less than 1.0% to 7-ACA.After having reacted, be cooled to below 10 degree, reaction solution moved into be equipped with in the there-necked flask of 300ml deionized water, drip sodium carbonate solution, be cooled to 10 ℃, stirred growing the grain 1 hour, filter, use the washing with acetone after drying to pH2～4;
The preparation of step 2 acid anhydrides
Methylene dichloride 150ml adds tetrazoleacetic acid 8.9g, cools to-50 ± 1 ℃; In 15 minutes, dripping triethylamine is stirred to tetrazoleacetic acid and all dissolves; Holding temperature-55 ± 1 ℃ drips pivaloyl chloride 8g, and reaction obtained the acid anhydrides solution for standby after 60 minutes under holding temperature-30 ± 1 ℃ temperature;
The acid of step 3 Cephazolin is synthetic
To methylene dichloride 180ml, add TDA23g, be cooled to-30 ± 2 ℃, in 30 minutes, drip tetramethyl guanidine then and all dissolve to TDA; Join TDA solution in the acid anhydrides solution reactor, controlled temperature-30 ± 1 ℃ reaction 1 hour adds water 300ml, transfers PH5～7 with triethylamine; Stir 15 minutes static layering, methylene dichloride addition entry 70ml transfers PH5～7 with triethylamine, static phase-splitting; Merge water, add gac 2g decolouring, stir 20 minutes filtration washing backs and merge water; Water is through the decolouring of aluminium sesquioxide pillar, and behind the collection water, adding weight ratio is ETHYLE ACETATE and the alcoholic acid mixed solvent 80ml of 0.5-1.5; Dripping hydrochloric acid is lowered the temperature 10～15 ℃ to PH1.3-1.6,1 hour after-filtration drying of growing the grain.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610282A (en) * | 2015-02-14 | 2015-05-13 | 石药集团中诺药业（石家庄）有限公司 | Method for purifying cefazolin acid |
| CN104892536A (en) * | 2015-06-18 | 2015-09-09 | 广州白云山天心制药股份有限公司 | N-(2, 2-dimethoxyethyl)-2-(1H-tetrazol-1-yl) amide and its preparation method |
| CN104910188A (en) * | 2015-05-26 | 2015-09-16 | 齐鲁安替制药有限公司 | Synthetic method of cefazolin acid |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
| CN109748926A (en) * | 2019-01-23 | 2019-05-14 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefazolin |
| CN110396103A (en) * | 2018-10-11 | 2019-11-01 | 广东金城金素制药有限公司 | Cefazolin sodium or combinations thereof object, preparation method and its preparation and genital system infection new indication |
| CN110759931A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity K |
| CN110790775A (en) * | 2019-10-30 | 2020-02-14 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity B |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610282A (en) * | 2015-02-14 | 2015-05-13 | 石药集团中诺药业（石家庄）有限公司 | Method for purifying cefazolin acid |
| CN104910188A (en) * | 2015-05-26 | 2015-09-16 | 齐鲁安替制药有限公司 | Synthetic method of cefazolin acid |
| CN104910188B (en) * | 2015-05-26 | 2017-07-04 | 齐鲁安替制药有限公司 | A kind of synthetic method of Cefazolin acid |
| CN104892536A (en) * | 2015-06-18 | 2015-09-09 | 广州白云山天心制药股份有限公司 | N-(2, 2-dimethoxyethyl)-2-(1H-tetrazol-1-yl) amide and its preparation method |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
| CN110396103A (en) * | 2018-10-11 | 2019-11-01 | 广东金城金素制药有限公司 | Cefazolin sodium or combinations thereof object, preparation method and its preparation and genital system infection new indication |
| CN109748926A (en) * | 2019-01-23 | 2019-05-14 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefazolin |
| CN110759931A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity K |
| CN110790775A (en) * | 2019-10-30 | 2020-02-14 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity B |
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| CN102617607B (en) | 2014-04-16 |
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Effective date of registration: 20221102 Address after: No. 68, Limin West 4th Street, Limin Development Zone, Harbin, Heilongjiang 150500 Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd. Patentee after: MEDSHINE DISCOVERY Inc. Address before: No. 109, Xuefu Road, Nangan, Harbin, Heilongjiang 150046 Patentee before: MEDSHINE DISCOVERY Inc. |