CN102617607B - Method for preparing cefazolin compounds - Google Patents
Method for preparing cefazolin compounds Download PDFInfo
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- CN102617607B CN102617607B CN201210093006.9A CN201210093006A CN102617607B CN 102617607 B CN102617607 B CN 102617607B CN 201210093006 A CN201210093006 A CN 201210093006A CN 102617607 B CN102617607 B CN 102617607B
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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 is (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, under Isodose, its Plasma Concentration is higher.The feature of this product is stronger to the effect of gram-negative bacteria, has advantages of 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 sensitive organism.
The preparation method of relevant Kefzol has many, as Chinese patent:
A preparation method for cephazolin sodium, application number: 201110214214
A synthetic method for 2-methyl-5-sulfydryl-1,3,4-thiadiazole, application number: 201110218412
A cefazolin sodium pentahydrate compound for variation route, application number: 200910169646
The preparation method of three intermediates of Kefzol, application number: 200410043639
The preparation method of Kefzol, application number: 00121531
The method of preparing Kefzol, application number: 96117398
But method of the prior art, organic solvent and the reagent with certain toxicity that uses more, deal with more difficult, environment is had to certain pollution, in addition, for obtaining product and the high route decontamination simultaneously of yield that purity is high, need in building-up process, use suitable solvent and reagent, the present invention, through screening, has found a kind of synthetic method, has solved the problems referred to above.
Summary of the invention:
The invention discloses a kind of preparation method who prepares Kefzol compound.Preparation method of the present invention comprises the following steps:
Synthesizing of step 1, three intermediates of sodium CEZ (TDA), thiadiazoles and 7-ACA reaction obtain, and reaction be take methylcarbonate as solvent, and boron trifluoride-methylcarbonate is catalyzer, with sodium carbonate, adjusts solution iso-electric point;
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, through the decolouring of aluminium sesquioxide pillar, is purified.
Wherein, in step 1, solvent for use is methylcarbonate; After reaction finishes, adjusting reaction solution PH agents useful for same is mineral alkali, the sodium carbonate of preferred environmental protection, boron trifluoride and 7-ACA weight ratio scope 0.7-1.3.
In step 3, need to drip hydrochloric acid to PH1.3-1.6, preferably 1.5, during Kefzol acid crystal, the disperse phase of employing is the mixed solvent of ethyl acetate and ethanol, ethyl acetate and ethanol mixed solvent weight ratio scope are 0.5-1.5.
The more original technology of novel method compares than following (contrast of Kefzol index)
| Batch | Content | Yield (always) | 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 environmental protection solvent.And solvent recovery process is simple, and the rate of recovery is high.Boron trifluoride and 7-ACA weight ratio scope 0.7-1.3.
2,, in TDA crystallisation process, adopt the sodium carbonate of environmental protection to adjust solution iso-electric point.
3, in Cephazolin acid building-up process, water adopts aluminium sesquioxide pillar to purify, and has improved the quality of product.
4, when Kefzol acid crystal, the disperse phase of employing is the mixed solvent of ethyl acetate and ethanol, has improved the crystalline form of product, improves again the quality of product simultaneously, and ethyl acetate and ethanol mixed solvent weight ratio scope are 0.5-1.5.
Method of the present invention significantly improves the more existing synthetic method of quality product.The method operation steps is short, and yield is high, and cost is low, is applicable to industrialized production.
Embodiment:
By the following examples, further illustrate the present invention, but not as limitation of the present invention.
Embodiment 1
Three intermediates of step 1 sodium CEZ (TDA) are synthetic,
In condensation tank, add 50g methylcarbonate, 69g boron trifluoride-methylcarbonate, opens stirring, in tank, drops into thiadiazoles 13g, and 7-ACA25g heats up simultaneously, and 30～40 ℃ of temperature of reaction are reacted to the residual of 7-ACA and are less than 1.0%.After having reacted, be cooled to below 10 degree, reaction solution is moved into and has been equipped with in the there-necked flask of 300ml deionized water, drip sodium carbonate solution to pH2～4, be cooled to 10 ℃, stir growing the grain 1 hour.Filter, with dry after washing with acetone.
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, at ℃ temperature of holding temperature-30 ± 1, reacts after 60 minutes and obtains acid anhydrides solution for standby.
The acid of step 3 Cephazolin is synthetic
To methylene dichloride 180ml, add TDA23g, be cooled to-30 ± 2 ℃, then in 30 minutes, drip tetramethyl guanidine and all dissolve to TDA.TDA solution is joined in acid anhydrides solution reactor, control temperature-30 ± 1 ℃ reaction 1 hour, add water 300ml, with triethylamine, adjust PH5～7, stir 15 minutes static layering, methylene dichloride is added to water 70ml, with triethylamine, adjust PH5～7, static phase-splitting, merge water, add gac 2g decolouring, stir and within 20 minutes, filter the rear water that merges of washing, water is through the decolouring of aluminium sesquioxide pillar, collect after water, adding weight ratio is the ethyl acetate of 0.5-1.5 and the mixed solvent 80ml of ethanol, drip hydrochloric acid to PH1.3-1.6, lower the temperature 10～15 ℃, growing the grain is filtration drying after 1 hour.
Claims (1)
1. a preparation method for Kefzol, comprises the following steps:
Step 1 7-amino-3-[[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) sulphur) methyl] cephamycin alkanoic acid synthetic,
In condensation tank, add 50g methylcarbonate, 69g boron trifluoride-methylcarbonate, opens stirring, in tank, drops into 2-sulfydryl-5-methyl isophthalic acid, 3,4-thiadiazoles 13g, 7-ACA25g heats up simultaneously, 30～40 ℃ of temperature of reaction, react to the residual of 7-ACA and are less than 1.0%
After having reacted, be cooled to below 10 ℃, reaction solution is moved into and has been equipped with in the there-necked flask of 300ml deionized water, drip sodium carbonate solution to pH2～4, be cooled to 10 ℃, stir growing the grain 1 hour, filter, with dry after washing with acetone;
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, at ℃ temperature of holding temperature-30 ± 1, reacts after 60 minutes and obtains acid anhydrides solution for standby;
The acid of step 3 Cephazolin is synthetic
To methylene dichloride 180ml, add 7-amino-3-[[(5-methyl isophthalic acid, 3, 4-thiadiazoles-2-yl) sulphur) methyl] cephamycin alkanoic acid 23g, be cooled to-30 ± 2 ℃, then in 30 minutes, drip tetramethyl guanidine to 7-amino-3-[[(5-methyl isophthalic acid, 3, 4-thiadiazoles-2-yl) sulphur) methyl] cephamycin alkanoic acid all dissolves, 7-amino-3-[[(5-methyl isophthalic acid, 3, 4-thiadiazoles-2-yl) sulphur) methyl] cephamycin alkanoic acid solution joins in acid anhydrides solution reactor, control temperature-30 ± 1 ℃ reaction 1 hour, add water 300ml, with triethylamine, adjust pH5～7, stir 15 minutes static layering, methylene dichloride is added to water 70ml, with triethylamine, adjust pH5～7, static phase-splitting, merge water, add gac 2g decolouring, stir and within 20 minutes, filter the rear water that merges of washing, water is through the decolouring of aluminium sesquioxide pillar, collect after water, adding weight ratio is 0.5-1.5 ethyl acetate and the mixed solvent 80ml of ethanol, drip hydrochloric acid to pH1.3-1.6, lower the temperature 10～15 ℃, growing the grain is filtration drying after 1 hour.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210093006.9A CN102617607B (en) | 2012-03-31 | 2012-03-31 | Method for preparing cefazolin compounds |
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| CN201210093006.9A CN102617607B (en) | 2012-03-31 | 2012-03-31 | Method for preparing cefazolin compounds |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104610282B (en) * | 2015-02-14 | 2017-03-15 | 石药集团中诺药业（石家庄）有限公司 | A kind of method of purification of cefazolin |
| 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 |
| CN104892536B (en) * | 2015-06-18 | 2017-10-17 | 广州白云山天心制药股份有限公司 | N (2,2 dimethoxy-ethyl) 2 (base of 1H tetrazoles 1) acid amides and preparation method thereof |
| CN105541870B (en) * | 2016-02-01 | 2018-01-16 | 广东金城金素制药有限公司 | A kind of former preparation method and its pharmaceutical preparation for developing quality brizolina |
| CN110396103B (en) * | 2018-10-11 | 2021-03-19 | 广东金城金素制药有限公司 | Cefazolin sodium or composition thereof, preparation method and preparation thereof, and new indications of reproductive system infection |
| CN109748926B (en) * | 2019-01-23 | 2020-04-28 | 华北制药河北华民药业有限责任公司 | Method for purifying cefazolin acid |
| CN110790775B (en) * | 2019-10-30 | 2022-05-10 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity B |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004020649A1 (en) * | 2002-08-30 | 2004-03-11 | Bioferma Murcia, S.A. | AN ENZYMATIC PROCESS FOR PREPARING β-LACTAMS |
| EP1416054A1 (en) * | 2002-10-31 | 2004-05-06 | Bioferma Murcia, S.A. | Simple enzymatic process for preparing cefazolin |
| CN1594321A (en) * | 2004-06-23 | 2005-03-16 | 哈药集团制药总厂 | Process for preparing cephazoline three-position intermediate |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
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2012
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004020649A1 (en) * | 2002-08-30 | 2004-03-11 | Bioferma Murcia, S.A. | AN ENZYMATIC PROCESS FOR PREPARING β-LACTAMS |
| EP1416054A1 (en) * | 2002-10-31 | 2004-05-06 | Bioferma Murcia, S.A. | Simple enzymatic process for preparing cefazolin |
| CN1594321A (en) * | 2004-06-23 | 2005-03-16 | 哈药集团制药总厂 | Process for preparing cephazoline three-position intermediate |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
Non-Patent Citations (3)
| Title |
|---|
| Alberto Palomo-coll，等.Efficient Procedure for C’-3 Substitution and C-7 N-acylation of 7-Aminocephalosporanic Acid (7-ACA): Synthesis of Cefazolin Antibiotic and Related Compounds.《Tetrahedron》.1985,第41卷(第22期),第5137-5138页. |
| Alberto Palomo-coll,等.Efficient Procedure for C’-3 Substitution and C-7 N-acylation of 7-Aminocephalosporanic Acid (7-ACA): Synthesis of Cefazolin Antibiotic and Related Compounds.《Tetrahedron》.1985,第41卷(第22期),第5137-5138页. * |
| 陈艳荣,等.头孢唑啉钠合成工艺改进.《现代食品与药品杂志》.2006,第16卷(第6期),第44-45页. * |
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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. |
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