CN112110939A - Preparation method of cephalothin lactone - Google Patents
Preparation method of cephalothin lactone Download PDFInfo
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- CN112110939A CN112110939A CN202010938584.2A CN202010938584A CN112110939A CN 112110939 A CN112110939 A CN 112110939A CN 202010938584 A CN202010938584 A CN 202010938584A CN 112110939 A CN112110939 A CN 112110939A
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- cephalothin
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- lactone
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- hydrolysis reaction
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- 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
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
- C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
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- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cephalothin lactone, which takes cephalothin acid as raw material, obtains deacetylated cephalothin through hydrolysis reaction, and then carries out ring-closure reaction under the action of catalyst to obtain cephalothin lactone. The invention provides a preparation method for efficiently obtaining cephalothin derivatives, which has high product purity, and the cephalothin derivatives are impurities possibly existing in cephalothin sodium, can provide reference substances or positioning substances for impurity research of medicines, and simultaneously provides an idea for developing new cephalothin products.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of cephalothin lactone.
Background
The cephalothin sodium is a broad-spectrum cephalosporin antibiotic widely used clinically. During the production process or the storage process of the cephalothin sodium, due to the characteristics of the cephalothin product, related derivatives can be generated, and corresponding impurities are needed for pharmaceutical research for effectively researching the product quality and optimizing the synthesis process. At present, the impurities are mainly obtained by separating from a spore product, and have the defects of small yield, complex operation, high cost, low production efficiency and the like.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method capable of efficiently obtaining cephalothin lactone.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of cephalothin lactone uses cephalothin acid as raw material, and obtains deacetylated cephalothin through hydrolysis reaction, and then carries out ring-closing reaction under the action of catalyst to obtain cephalothin lactone.
Preferably, the hydrolysis reaction is carried out at a pH ≥ 10.
Preferably, the hydrolysis reaction is carried out at-30 to-10 ℃, more preferably-25 to-18 ℃.
Further preferably, the pH is adjusted by using an alkaline solution, wherein the alkaline solution is a sodium hydroxide solution or a potassium hydroxide solution with the mass percentage concentration of 10-30%.
Preferably, the specific method of the hydrolysis reaction is as follows: adding the cephalothin acid, water and solvent into a reaction container, cooling to-30-10 ℃, dropwise adding an alkaline solution to adjust the pH value to be more than or equal to 10, and controlling the temperature to be-30-10 ℃ to carry out the hydrolysis reaction.
Further preferably, the feeding mass ratio of the cephalothin acid to the water to the solvent is 1: 5-15: 1-5, and more preferably 1: 8-12: 1.5-3.5.
Further preferably, the temperature is reduced to-25 to-15 ℃.
Further preferably, the time of the hydrolysis reaction is controlled to be 30-60 min, and further preferably 40-50 min.
Further preferably, the solvent is methanol or ethanol.
Preferably, after the hydrolysis reaction is finished, adjusting the pH to 2-3, controlling the temperature to be 5-15 ℃, extracting by using an organic solvent, and carrying out the ring-closure reaction after organic phases are combined.
Further preferably, glacial acetic acid solution with the mass percentage concentration of 70-90% or hydrochloric acid solution with the mass percentage concentration of 1-3N is adopted to adjust the pH value.
Further preferably, the organic solvent is dichloromethane or ethyl acetate.
Preferably, the catalyst is 4-methylpyridine or 4-N, N dimethylaminopyridine.
Further preferably, the addition amount of the catalyst is 1-2% of the feeding mass of the cephalothin acid.
Preferably, the reaction temperature of the esterification reaction is 0-25 ℃, and further preferably 0-20 ℃.
Preferably, the ring closure reaction is also carried out in the presence of a dehydrating agent.
Further preferably, the dehydrating agent is Dicyclohexylcarbodiimide (DCC).
Further preferably, the addition amount of the dehydrating agent is 0.5-0.8 time of the feeding mass of the cephalothin acid.
Preferably, the ring closure reaction time is 0.8-1.2 h.
Preferably, the preparation method further comprises the step of carrying out post-treatment on the reaction system after the reaction is finished, wherein the post-treatment method comprises the steps of filtering, reduced pressure distillation, crystallization, washing and vacuum drying.
Further preferably, after the reaction is completed and before the post-treatment, the temperature of the reaction system is adjusted to 8-12 ℃.
In the invention, the structural formula of the cephalothin acid is shown as
Its chemical name is 3- (acetoxymethyl) -8-oxo-7- [ (2-thiophen-2-ylacetyl) amino]-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-carboxylic acid.
In the invention, the structural formula of the cephalothin lactone is shown in the specification
The chemical name is N- [3, 11-dioxo-10-oxa-6-thia-2-azatricyclo [6.3.0.02, 5]Undec-1 (8) -en-4-yl]-2-thiophen-2-ylacetamide.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides a preparation method for efficiently obtaining cephalothin derivatives, which has high product purity, and the cephalothin derivatives are impurities possibly existing in cephalothin sodium, can provide reference substances or positioning substances for impurity research of medicines, and simultaneously provides an idea for developing new cephalothin products.
Detailed Description
The present invention will be further described with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry. The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.
Example 1
Adding 30g of cephalothin acid (3- (acetoxymethyl) -8-oxo-7- [ (2-thiophen-2-ylacetyl) amino ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid), 300ml of purified water and 100ml of methanol into a reaction bottle, cooling to-18 ℃, dropwise adding 50g of 15% sodium hydroxide solution, controlling the pH value to be more than or equal to 10, stirring and reacting at the temperature of-20 +/-2 ℃ for 45min, neutralizing the pH value to be 2-3 with 80% glacial acetic acid solution, controlling the pH value to be 5-15 ℃, adding 300ml of ethyl acetate for extraction, combining organic phases, adding 0.5g of 4-methylpyridine and 20g of DCC as catalysts, stirring and reacting for 1hr, cooling to 10 +/-2 ℃, filtering, distilling the filtrate under reduced pressure to obtain a solution with the volume of about 200ml, the crystals were cooled, filtered, washed with ethyl acetate and dried under vacuum to give cephalothin lactone (N- [3, 11-dioxo-10-oxa-6-thia-2-azatricyclo [6.3.0.02, 5] undec-1 (8) -en-4-yl ] -2-thiophen-2-ylacetamide) in an amount of about 18.5g with a purity of 97.9%.
The present invention has been described in detail in order to enable those skilled in the art to understand the invention and to practice it, and it is not intended to limit the scope of the invention, and all equivalent changes and modifications made according to the spirit of the present invention should be covered by the present invention.
Claims (10)
1. A preparation method of cephalothin lactone is characterized in that: the method takes cephalothin acid as a raw material, deacetylated cephalothin is obtained through hydrolysis reaction, and then, cephalothin lactone is obtained through ring closure reaction under the action of a catalyst.
2. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: the hydrolysis reaction is carried out under the condition that the pH value is more than or equal to 10, and the hydrolysis reaction is carried out under the condition of-30 to-10 ℃.
3. The process for the preparation of cephalothin lactone according to claim 2, characterized in that: and adjusting the pH value by adopting an alkaline solution, wherein the alkaline solution is a sodium hydroxide solution or a potassium hydroxide solution with the mass percentage concentration of 10-30%.
4. The process for the preparation of cephalothin lactone according to any of claims 1 to 3, characterized in that: the specific method of the hydrolysis reaction comprises the following steps: adding the cephalothin acid, water and solvent into a reaction container, cooling to-30-10 ℃, dropwise adding an alkaline solution to adjust the pH value to be more than or equal to 10, and controlling the temperature to be-30-10 ℃ to carry out the hydrolysis reaction.
5. The process for producing cephalothin lactone according to claim 4, characterized in that: the feeding mass ratio of the cephalothin acid to the water to the solvent is 1: 5-15: 1-5.
6. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: after the hydrolysis reaction is finished, adjusting the pH to 2-3, controlling the temperature to be 5-15 ℃, extracting by using an organic solvent, and carrying out the ring-closing reaction after organic phases are combined; wherein the organic solvent is dichloromethane or ethyl acetate.
7. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: the catalyst is 4-methylpyridine or 4-N, N dimethylamino pyridine; the reaction temperature of the esterification reaction is 0-25 ℃.
8. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: the ring closure reaction is also carried out in the presence of a dehydrating agent.
9. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: the preparation method also comprises the step of carrying out post-treatment on the reaction system after the reaction is finished, wherein the post-treatment method comprises the steps of filtering, reduced pressure distillation, crystallization, washing and vacuum drying.
10. The process for the preparation of cephalothin lactone according to claim 1, characterized in that: the structural formula of the cephalothin acid is shown as
The structural formula of the cephalothin lactone is shown as
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202010938584.2A CN112110939A (en) | 2020-09-09 | 2020-09-09 | Preparation method of cephalothin lactone |
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| CN202010938584.2A CN112110939A (en) | 2020-09-09 | 2020-09-09 | Preparation method of cephalothin lactone |
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| CN202010938584.2A Pending CN112110939A (en) | 2020-09-09 | 2020-09-09 | Preparation method of cephalothin lactone |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204557A (en) * | 2019-07-02 | 2019-09-06 | 苏州盛达药业有限公司 | A kind of preparation method of Mandokef sodio-derivative |
| CN110684039A (en) * | 2019-09-23 | 2020-01-14 | 浙江普洛得邦制药有限公司 | Preparation method of cefoxitin lactone |
-
2020
- 2020-09-09 CN CN202010938584.2A patent/CN112110939A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204557A (en) * | 2019-07-02 | 2019-09-06 | 苏州盛达药业有限公司 | A kind of preparation method of Mandokef sodio-derivative |
| CN110684039A (en) * | 2019-09-23 | 2020-01-14 | 浙江普洛得邦制药有限公司 | Preparation method of cefoxitin lactone |
Non-Patent Citations (2)
| Title |
|---|
| CHAUVETTE, ROBERT R.等: "Chemistry of cephalosporin antibiotics. V. Amides and esters of cephalothin", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 李强等: "头孢曲松内酯的合成及遗传毒性研究", 《中国抗生素杂志》 * |
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