CN103012437A - Method for preparing cefoxitin acid as antibacterial medicament - Google Patents
Method for preparing cefoxitin acid as antibacterial medicament Download PDFInfo
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- CN103012437A CN103012437A CN2012105123988A CN201210512398A CN103012437A CN 103012437 A CN103012437 A CN 103012437A CN 2012105123988 A CN2012105123988 A CN 2012105123988A CN 201210512398 A CN201210512398 A CN 201210512398A CN 103012437 A CN103012437 A CN 103012437A
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Abstract
The invention discloses a method for preparing cefoxitin acid as an antibacterial medicament, comprising the following steps: (1) dissolving 7-aminocephalosporanic acid as a raw material into an alkaline solution, stirring after the alkaline solution becomes clear, adding ethyl acetate, adjusting the pH value, and separating out a crystal to obtain a compound I; (2) carrying out a reaction on the compound I, NBS (N-bromosuccinimide) and sodium methoxide, and introducing a methoxyl to the site 7 of the compound 1 to obtain a mixed solution containing a compound II; (3) carrying out a reaction on the compound II and a 2-thienyl acetylation reagent, introducing thienyl acetyl, and separating out a crystal to obtain a compound III; and (4) enabling the compound III to act with an ammonia methoxyl acylation reagent, and introducing a carbamoyl-methoxyl to the site 3 of the compound III to obtain the cefoxitin acid. The method is simple in preparation process and low in cost, is easy to implement, is suitable for large-scale production, adopts the low-cost raw materials which are easy to purchase and improves the yield of the cefoxitin acid significantly.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of preparation method of antibacterial drugs cefoxitin acid.
Background technology
The chemical name of cefoxitin acid is: (6R, 7S)-3-(methylol)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid; Belong to s-generation cephalosporin analog antibiotic, its structural formula be for:
This pharmaceutical intermediate is developed by U.S. Merck company.Because cefoxitin contains the constructional feature of 7 α-methoxyl group, makes it have very high resistivity to bacteriogenic β-lactamase, thereby the stable cefoxitin of β-lactamase is had huge market potential.
The route of at present synthetic cefoxitin mainly contains:
1) take cephamycin C as raw material, first the amino on its carboxylic acid side chain is modified, then its tetra-atomic ring is modified.But the reaction of this class all exist technique loaded down with trivial details, need the shortcoming such as noble metal catalyst, therefore never satisfy the demand of industrialized production.
2) take the 7-ACA or derivatives thereof as raw material, through amino conversion, bromination, azide, hydro-reduction, deprotection etc., the method step is many, cost is high, has environmental protection and potential safety hazard.
3) take 7-MAC as raw material, modify first the C7 bit amino side chain of 7-MAC, then modify the side chain on the C3 position, although this class methods synthesis step is simplified, the 7-MAC valency is expensive and be difficult to obtain, therefore also be not applied to industrialization always.
Summary of the invention
Purpose of the present invention is for providing a kind of preparation method of antibacterial drugs cefoxitin acid, and raw materials cost of the present invention is low, and yield is high; Reaction conditions is gentle, the powder good crystallinity, and the synthetic powder granularity is little; Preparation process is simple, and is easy to implement, can reduce introducing impurity; Required equipment is simple, is more suitable for scale operation.
The preparation method of antibacterial drugs cefoxitin acid of the present invention, step is as follows:
(1) goes the preparation of acetyl 7-amino-cephalosporanic acid
Take 7-amino-cephalosporanic acid as raw material, in basic solution, be hydrolyzed, molten clear rear the stirring regulated the pH value after the adding ethyl acetate, and crystallize out obtains chemical compounds I;
(2) preparation of compound ii
Chemical compounds I and NBS and sodium methylate reaction, 7 introducing methoxyl groups at chemical compounds I obtain containing the compound ii mixed solution;
(3) preparation of compound III
Compound ii and 2-thiophene acetyl reagent react, crystallization behind the introducing thiophene acetyl obtains the compound III;
(4) cefoxitin is synthetic
Compound III and the effect of ammonia methoxy acylating reagent, 3 introducing carboxamide methoxyl groups in the compound III obtain cefoxitin.
Wherein,
The chemical equation of step (1) is:
In step (1), the hydrolysis churning time is 30～60min.
Concentration of sodium hydroxide solution in the described step (1) is 20%～40%.
PH is 2.5～3.5 after regulating in the described step (1).
The chemical equation of step (2) is:
In step (2), before chemical compounds I and NBS and the sodium methylate reaction, the mixed solution that will go first the acetyl 7-amino-cephalosporanic acid to join methylene dichloride and methyl alcohol stirs, and adds methylsulfonic acid.Wherein, the volume ratio of methylene dichloride and methyl alcohol is 8～12:1.
Chemical compounds I in the described step (2) and the mol ratio of NBS are 1:1～2.5; The mol ratio of chemical compounds I and sodium methylate is 1:20～35.
Add later on stirring reaction 1～6h of sodium methylate in the described step (2).
The chemical equation of step (3) is:
2-thiophene acetyl reagent in the described step (3) is: 2-thiophene acetic acid, 2-thiophen acetyl chloride, 2-thiophene acetyl bromide, 2-thiophene acetic acid acid anhydride, 2-thiophene acetic acid methyl esters or 2-thiophene acetic acid ethyl ester.
Compound ii mixed solution in the described step (3) and the volume ratio of purified water are 1:2～4.
Step (4) stirs and cooling for the compound III is dissolved in the tetrahydrofuran (THF), drips cold ammonia methoxy acylating reagent, is stirred to abundant reaction.The purified water that adds in the reaction solution fully stirs, and adds ethyl acetate, filters to get clear filtrate, adds the 8-15% sodium chloride solution, stirs 25-35min.Drip saturated sodium carbonate solution and transfer pH, tell organic phase, drip dilute hydrochloric acid to pH=1.5～3.0 to water and separate out white crystal, obtain cefoxitin.
The reactional equation of step (4) be for:
Ammonia methoxy acylating reagent in the described step (4) is chloro sulfonyl isocyanate, bromine sulfonic group isocyanic ester, chloracetyl isocyanic ester, three chloroethyl isocyanates or chloro-phenyl-sulfonylisocyanates.
PH that saturated sodium carbonate is transferred in the described step (4) is 6.0～7.0, and it is 1.5～3.0 that the machine of telling is regulated the pH value mutually afterwards.
The present invention compared with prior art has following beneficial effect:
(1) the method raw materials cost is low, and yield is high;
(2) the method reaction conditions is gentle, the powder good crystallinity, and the synthetic powder granularity is little; Reduce the chance of introducing impurity, do not affect the purity of product;
(3) the method required equipment is simple, and reaction process is simple, and is easy to implement, is more suitable for scale operation.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
A kind of preparation method of antibacterial drugs cefoxitin comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
7-ACA60g is added in the reaction vessel, be scattered in the 350mL water, add 25% sodium hydroxide solution, pH value of solution is transferred to 8.1, and the control temperature is 5 ℃ of reactions that are hydrolyzed, and 45min is stirred in molten clear rear continuation, add ethyl acetate 125mL, stir 15min, then drip the dilute hydrochloric acid of 1.2mol/L, regulating pH is 2.7, crystallize out, oven dry obtains acetyl 7-amino-cephalosporanic acid 49.9g, yield 98.34%;
The preparation of compound ii
The 49.9g chemical compounds I is joined in the mixed solution of 360mL methylene dichloride and 30mL methyl alcohol, be cooled to-23 ℃, stir 20min.Add methylsulfonic acid 2.082g, cool off-55 ℃, add NBS 77.15g in batches, add sodium methylate 292.55g, fully stir 3h, every 0.5h sampling high performance liquid chromatography detection compound I residual reaction less than 1% time finishes, obtain containing the compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under the rapid stirring condition, drip 2-thiophen acetyl chloride 39.87g in the compound ii mixed solution, temperature is controlled at 12 ℃, and 2.5h drips, then continue insulated and stirred 3h, add 20% sodium hydroxide solution, pH value of solution is transferred to 7.5, drip purified water 150mL, solution becomes is muddy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration washs with the methylene dichloride of cooling and the mixed solution of methyl alcohol, and the baking material obtains compound III 78.49g, yield 95.2%;
Synthesizing of cefoxitin
70g compound III is dissolved in the 300mL tetrahydrofuran (THF), stirs and be cooled to-42 ℃, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to abundant reaction 1.5h.The purified water 180mL that adds 0 ℃ in the reaction solution fully stirs, and adds ethyl acetate 650mL, filter, get clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and transfer pH=7, fully stir 1.5h, tell organic phase, drip dilute hydrochloric acid to pH=3 to water, separate out white crystal, insulation growing the grain 30min, the baking material obtains cefoxitin 64.40g, yield 92%.
Embodiment 2
A kind of preparation method of antibacterial drugs cefoxitin comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
In reaction vessel, add 7-ACA 60g, it is scattered in the 350mL water, the sodium hydroxide solution of adding 20% is transferred to 8.2 with pH value of solution, and the control temperature is 2 ℃ of reactions that are hydrolyzed, the molten clear rear 60min that continues to stir, add ethyl acetate 125mL, stir 15min, the dilute hydrochloric acid that then drips 1.2mol/L is regulated pH=3, crystallize out, oven dry obtains acetyl 7-amino-cephalosporanic acid 50.1g, yield 98.73%.
The preparation of compound ii
The 50.01g chemical compounds I is joined in the mixed solution of 300mL methylene dichloride and 36mL methyl alcohol, be cooled to-25 ℃, stir 20min.Add methylsulfonic acid 2.091g, cool off-60 ℃, add NBS 39.01g in batches, add sodium methylate 352.2g, fully stir 6h, every 0.5h sampling high performance liquid chromatography detection compound I residual reaction less than 1% time finishes, obtain containing the compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under the rapid stirring condition, drip 2-thiophen acetyl chloride 40.04g in the compound ii mixed solution, temperature is controlled at 10 ℃, and 2.5h drips, then continue insulated and stirred 3h, add 20% sodium hydroxide solution, pH value of solution is transferred to 7.5, drip purified water 220mL, solution becomes is muddy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration washs with the methylene dichloride of cooling and the mixed solution of methyl alcohol, and the baking material obtains compound III 79.32g, yield 95.8%;
Synthesizing of cefoxitin
70g compound III is dissolved in the 300mL tetrahydrofuran (THF), stirs and be cooled to-48 ℃, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to abundant reaction 1.5h.The purified water 180mL that adds 0 ℃ in the reaction solution fully stirs, and adds ethyl acetate 650mL, filter, get clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and transfer pH=6.4, fully stir 1.5h, tell organic phase, drip dilute hydrochloric acid to pH=2.0 to water, separate out white crystal, insulation growing the grain 30min, the baking material obtains cefoxitin 65.38g, yield 93.4%.
Embodiment 3
A kind of preparation method of antibacterial drugs cefoxitin comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
In reaction vessel, add 7-ACA60g, it is scattered in the 350mL water, the sodium hydroxide solution of adding 30% is transferred to 8.4 with pH value of solution, and the control temperature is 4 ℃ of reactions that are hydrolyzed, the molten clear rear 30min that continues to stir, add ethyl acetate 125mL, stir 15min, then drip dilute hydrochloric acid (1.2mol/L) and regulate pH=3.4, crystallize out, oven dry obtains acetyl 7-amino-cephalosporanic acid 50.3g, yield 99.12%;
The preparation of compound ii
The 50.3g chemical compounds I is joined in the mixed solution of 360mL methylene dichloride and 36mL methyl alcohol, be cooled to-20 ℃, stir 20min.Add methylsulfonic acid 2.099g, cool off-55 ℃, add NBS 59.22g in batches, add sodium methylate 294.84(401.45) g, fully stir 4h, every 0.5h sampling high performance liquid chromatography detection compound I residual reaction less than 1% time finishes, and obtains containing the compound ii mixed solution, is directly used in next step reaction;
The preparation of compound III
Under the rapid stirring condition, drip 2-thiophen acetyl chloride 40.19g in the compound ii mixed solution, temperature is controlled at 6 ℃, and 2.5h drips, then continue insulated and stirred 3h, add 20% sodium hydroxide solution, pH value of solution is transferred to 7.5, drip purified water 150mL, solution becomes is muddy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration washs with the methylene dichloride of cooling and the mixed solution of methyl alcohol, and the baking material obtains compound III 79.37g, yield 95.5%;
Synthesizing of cefoxitin
70g compound III is dissolved in the 300mL tetrahydrofuran (THF), stirs and be cooled to-45 ℃, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to abundant reaction 1.5h.The purified water 180mL that adds 0 ℃ in the reaction solution fully stirs, and adds ethyl acetate 650mL, filter, get clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and transfer pH=6, fully stir 1.5h, tell organic phase, drip dilute hydrochloric acid to pH=2.1 to water, separate out white crystal, insulation growing the grain 30min, the baking material obtains cefoxitin 65.87g, yield 94.1%.
Embodiment 4
A kind of preparation method of antibacterial drugs cefoxitin comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
In reaction vessel, add 7-ACA60g, it is scattered in the 350mL water, the sodium hydroxide solution of adding 40% is transferred to 8.4 with pH value of solution, and the control temperature is 3 ℃ of reactions that are hydrolyzed, the molten clear rear 50min that continues to stir adds ethyl acetate 125mL, stirs 15min, then drip the dilute hydrochloric acid of 1.2mol/L, regulate pH=2.5, crystallize out, oven dry, obtain acetyl 7-amino-cephalosporanic acid 49.8g, yield 98.14%;
The preparation of compound ii
The 49.8g chemical compounds I is joined in the mixed solution of 430mL methylene dichloride and 36mL methyl alcohol, be cooled to-21 ℃, stir 20min.Add methylsulfonic acid 2.079g, cool off-40 ℃, add NBS 87.00g in batches, add sodium methylate 292.00g, fully stir 2h, every 0.5h sampling high performance liquid chromatography detection compound I residual reaction less than 1% time finishes, obtain containing the compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under the rapid stirring condition, drip 2-thiophen acetyl chloride 39.80g in the compound ii mixed solution, temperature is controlled at 14 ℃, and 2.5h drips, then continue insulated and stirred 3h, add 20% sodium hydroxide solution, pH value of solution is transferred to 7.5, drip purified water 180mL, solution becomes is muddy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration washs with the methylene dichloride of cooling and the mixed solution of methyl alcohol, and the baking material obtains compound III 79g, yield 96%;
Synthesizing of cefoxitin
70g compound III is dissolved in the 300mL tetrahydrofuran (THF), stirs and be cooled to-42 ℃, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to abundant reaction 1.5h.The purified water 180mL that adds 0 ℃ in the reaction solution fully stirs, and adds ethyl acetate 650mL, filter, get clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and transfer pH=6.6, fully stir 1.5h, tell organic phase, drip dilute hydrochloric acid to pH=1.5 to water, separate out white crystal, insulation growing the grain 30min, the baking material obtains cefoxitin 64.96g, yield 92.8%.
Claims (10)
1. the preparation method of an antibacterial drugs cefoxitin acid is characterized in that, step is as follows:
(1) goes the preparation of acetyl 7-amino-cephalosporanic acid
Take 7-amino-cephalosporanic acid as raw material, in basic solution, be hydrolyzed, molten clear rear the stirring regulated the pH value after the adding ethyl acetate, and crystallize out obtains chemical compounds I;
(2) preparation of compound ii
Chemical compounds I and NBS and sodium methylate reaction, 7 introducing methoxyl groups at chemical compounds I obtain containing the compound ii mixed solution;
(3) preparation of compound III
Compound ii and 2-thiophene acetyl reagent react, crystallization behind the introducing thiophene acetyl obtains the compound III;
(4) cefoxitin is synthetic
Compound III and the effect of ammonia methoxy acylating reagent, 3 introducing carboxamide methoxyl groups in the compound III obtain cefoxitin.
2. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, in the described step (1), basic solution is that concentration is 20%～40% sodium hydroxide solution; Regulator solution pH value is 2.5～3.5.
3. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, described step (1) hydrolysis churning time is 30～60min.
4. the preparation method of antibacterial drugs cefoxitin acid according to claim 1, it is characterized in that, chemical compounds I in the described step (2) reacts with NBS and sodium methylate after being dissolved in first methylene dichloride and methyl alcohol again, and wherein, the volume ratio of methylene dichloride and methyl alcohol is 8～12:1.
5. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, the mol ratio of chemical compounds I and sodium methylate is 1:20～35; The mol ratio of chemical compounds I and NBS is 1:1～2.5.
6. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, adds later on stirring reaction 1～6h of NBS and sodium methylate in the described step (2).
7. the preparation method of antibacterial drugs cefoxitin acid according to claim 1; it is characterized in that, the 2-thiophene acetyl reagent in the described step (3) is: 2-thiophene acetic acid, 2-thiophen acetyl chloride, 2-thiophene acetyl bromide, 2-thiophene acetic acid acid anhydride, 2-thiophene acetic acid methyl esters or 2-thiophene acetic acid ethyl ester.
8. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, the Crystallization Process in the described step (3), and the volume ratio of compound ii mixed solution and purified water is 1:2～4.
9. the preparation method of antibacterial drugs cefoxitin acid according to claim 1; it is characterized in that, the ammonia methoxy acylating reagent in the described step (4) is chloro sulfonyl isocyanate, bromine sulfonic group isocyanic ester, chloracetyl isocyanic ester, three chloroethyl isocyanates or chloro-phenyl-sulfonylisocyanates.
10. the preparation method of antibacterial drugs cefoxitin acid according to claim 1 is characterized in that, regulating pH with saturated sodium carbonate in the described step (4) is 6.0～7.0; It is 1.5～3 that the machine of telling is regulated the pH value mutually afterwards.
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| CN104072521A (en) * | 2014-06-27 | 2014-10-01 | 广东省石油化工研究院 | Preparation method for cefoxitin acid |
| CN105385746A (en) * | 2015-11-02 | 2016-03-09 | 四川清山绿水实业发展有限公司 | Method for synthesizing cefoxitin acid |
| CN108440568A (en) * | 2018-04-11 | 2018-08-24 | 广东立国制药有限公司 | A kind of preparation method of descarbamoyl cefuroxime |
| CN110590814A (en) * | 2019-09-29 | 2019-12-20 | 天津力生制药股份有限公司 | Synthetic method of dimer impurity generated in production of cefazolin sodium |
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| CN110590814A (en) * | 2019-09-29 | 2019-12-20 | 天津力生制药股份有限公司 | Synthetic method of dimer impurity generated in production of cefazolin sodium |
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Denomination of invention: Preparation method of antibacterial cefoxitanic acid Effective date of registration: 20211216 Granted publication date: 20150805 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |
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Date of cancellation: 20220721 Granted publication date: 20150805 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |