CN103012437B - The preparation method of antibacterial drugs cefoxitin acid - Google Patents
The preparation method of antibacterial drugs cefoxitin acid Download PDFInfo
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- CN103012437B CN103012437B CN201210512398.8A CN201210512398A CN103012437B CN 103012437 B CN103012437 B CN 103012437B CN 201210512398 A CN201210512398 A CN 201210512398A CN 103012437 B CN103012437 B CN 103012437B
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Abstract
The invention discloses a kind of preparation method of antibacterial drugs cefoxitin acid, step is: (1) is raw material with 7-amino-cephalosporanic acid, is hydrolyzed in basic solution, molten clear rear stirring, add adjust ph after ethyl acetate, crystallize out, obtains chemical compounds I; Chemical compounds I and NBS and sodium methylate react, and introduce methoxyl groups, obtain containing compound ii mixed solution for 7 at chemical compounds I; Compound ii and 2-thiophene acetyl reagent react, crystallization after introducing thiophene acetyl, obtains compound III; Compound III and the effect of ammonia methoxy acylating reagent, introduce carboxamide methoxyl group, obtain cefoxitin for 3 in compound III; Preparation process of the present invention is simple, and easy to implement, effectively raise yield, raw material is cheaply easily purchased, and reduces cost, is applicable to producing greatly.
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 Merck company of the U.S..Because cefoxitin contains the constructional feature of 7 α-methoxyl group, make it have very high resistivity to bacteriogenic β-lactamase, thus to the cefoxitin that β-lactamase is stable, there is huge market potential.
The route of current synthesis 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 also exist technique loaded down with trivial details, need the shortcomings such as noble metal catalyst, therefore never meet the demand of industrialized production.
2) with 7-ACA or derivatives thereof for raw material, through amino conversion, bromination, azide, hydro-reduction, deprotection etc., the method step is many, cost is high, there is environmental protection and potential safety hazard.
3) take 7-MAC as raw material, first modify the C7 bit amino side chain of 7-MAC, then modify the side chain on C3 position, although this class methods synthesis step comparatively simplifies, and 7-MAC valency is expensive and be difficult to obtain, therefore be not also applied to industrialization always.
Summary of the invention
Object 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, and powder crystallinity is good, and synthetic powder granularity is little; Preparation process is simple, 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) preparation of acetyl 7-amino-cephalosporanic acid is gone
Be raw material with 7-amino-cephalosporanic acid, be hydrolyzed in basic solution, molten clear after stir, add adjust ph after ethyl acetate, crystallize out, obtains chemical compounds I;
(2) preparation of compound ii
Chemical compounds I and NBS and sodium methylate react, and introduce methoxyl groups, obtain containing compound ii mixed solution for 7 at chemical compounds I;
(3) preparation of compound III
Compound ii and 2-thiophene acetyl reagent react, crystallization after introducing thiophene acetyl, obtains compound III;
(4) synthesis of cefoxitin
Compound III and the effect of ammonia methoxy acylating reagent, introduce carboxamide methoxyl group, obtain cefoxitin for 3 in compound III.
Wherein,
The chemical equation of step (1) is:
In step (1), being hydrolyzed churning time is 30 ~ 60min.
Concentration of sodium hydroxide solution in described step (1) is 20% ~ 40%.
After regulating in described step (1), solution ph is 2.5 ~ 3.5.
The chemical equation of step (2) is:
In step (2), before chemical compounds I and NBS and sodium methylate react, first the mixed solution going acetyl 7-amino-cephalosporanic acid to join methylene dichloride and methyl alcohol is stirred, add methylsulfonic acid.Wherein, the volume ratio of methylene dichloride and methyl alcohol is 8 ~ 12:1.
Chemical compounds I in 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.
Sodium methylate stirring reaction 1 ~ 6h is later added in described step (2).
The chemical equation of step (3) is:
2-thiophene acetyl reagent in described step (3) is: 2-thiophene acetic acid, 2-thiophen acetyl chloride, 2-thiophenacetyl bromine, 2-thiophene acetic acid acid anhydride, 2-thiophene acetic acid methyl esters or 2-thiophene acetic acid ethyl ester.
Compound ii mixed solution in described step (3) and the volume ratio of purified water are 1:2 ~ 4.
Step (4), for be dissolved in tetrahydrofuran (THF) by compound III, to stir and lowers the temperature, and drips cold ammonia methoxy acylating reagent, is stirred to abundant reaction.The purified water added in reaction solution, fully stirs, and adds ethyl acetate, filters to obtain clear filtrate, adds 8-15% sodium chloride solution, stirs 25-35min.Drip saturated sodium carbonate solution and adjust pH, separate organic phase, drip dilute hydrochloric acid to aqueous phase and separate out white crystal to pH=1.5 ~ 3.0, obtain cefoxitin.
The reactional equation of step (4) be for:
Ammonia methoxy acylating reagent in described step (4) is chloro sulfonyl isocyanate, bromine sulfonic group isocyanic ester, chloracetyl isocyanic ester, trichloroethyl isocyanic ester or Chlorophenylsulfonyl isocyanic ester.
PH that saturated sodium carbonate is adjusted in described step (4) is 6.0 ~ 7.0, and the machine separated mutually rear adjust ph is 1.5 ~ 3.0.
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, and powder crystallinity is good, and synthetic powder granularity is little; Reduce the chance introducing impurity, do not affect the purity of product;
(3) the method required equipment is simple, and reaction process is simple, easy to implement, is more suitable for scale operation.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
A preparation method for antibacterial drugs cefoxitin, comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
7-ACA60g is added in reaction vessel, be scattered in 350mL water, add the sodium hydroxide solution of 25%, pH value of solution is transferred to 8.1, and control temperature is 5 DEG C of reactions that are hydrolyzed, and molten clear rear continuation stirs 45min, add ethyl acetate 125mL, stir 15min, then drip the dilute hydrochloric acid of 1.2mol/L, regulate pH to be 2.7, crystallize out, dry, obtain acetyl 7-amino-cephalosporanic acid 49.9g, yield 98.34%;
The preparation of compound ii
49.9g chemical compounds I is joined in the mixed solution of 360mL methylene dichloride and 30mL methyl alcohol, be cooled to-23 DEG C, stir 20min.Add methylsulfonic acid 2.082g, cool-55 DEG C, add NBS 77.15g in batches, add sodium methylate 292.55g, fully stir 3h, every 0.5h sample high performance liquid chromatography detection compound I residual when being less than 1% reaction terminate, obtain containing compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under rapid mixing conditions, in compound ii mixed solution, drip 2-thiophen acetyl chloride 39.87g, temperature controls at 12 DEG C, and 2.5h drips, then continue insulated and stirred 3h, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 7.5, drip purified water 150mL, solution turned cloudy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration, with the methylene dichloride of cooling and the mixed solution washing of methyl alcohol, dry material, obtain compound III 78.49g, yield 95.2%;
The synthesis of cefoxitin
70g compound III is dissolved in 300mL tetrahydrofuran (THF), stirs and be cooled to-42 DEG C, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to and fully react 1.5h.In reaction solution, add the purified water 180mL of 0 DEG C, fully stir, add ethyl acetate 650mL, filter, obtain clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and adjust pH=7, fully stir 1.5h, separate organic phase, drip dilute hydrochloric acid to pH=3 to aqueous phase, separate out white crystal, insulation growing the grain 30min, dry material, obtain cefoxitin 64.40g, yield 92%.
Embodiment 2
A preparation method for antibacterial drugs cefoxitin, comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
To in reaction vessel, add 7-ACA 60g, be scattered in 350mL water, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 8.2, control temperature is 2 DEG C of reactions that are hydrolyzed, molten clear rear continuation stirs 60min, add ethyl acetate 125mL, stir 15min, the dilute hydrochloric acid then dripping 1.2mol/L regulates pH=3, crystallize out, dry, obtain acetyl 7-amino-cephalosporanic acid 50.1g, yield 98.73%.
The preparation of compound ii
50.01g chemical compounds I is joined in the mixed solution of 300mL methylene dichloride and 36mL methyl alcohol, be cooled to-25 DEG C, stir 20min.Add methylsulfonic acid 2.091g, cool-60 DEG C, add NBS 39.01g in batches, add sodium methylate 352.2g, fully stir 6h, every 0.5h sample high performance liquid chromatography detection compound I residual when being less than 1% reaction terminate, obtain containing compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under rapid mixing conditions, in compound ii mixed solution, drip 2-thiophen acetyl chloride 40.04g, temperature controls at 10 DEG C, and 2.5h drips, then continue insulated and stirred 3h, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 7.5, drip purified water 220mL, solution turned cloudy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration, with the methylene dichloride of cooling and the mixed solution washing of methyl alcohol, dry material, obtain compound III 79.32g, yield 95.8%;
The synthesis of cefoxitin
70g compound III is dissolved in 300mL tetrahydrofuran (THF), stirs and be cooled to-48 DEG C, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to and fully react 1.5h.In reaction solution, add the purified water 180mL of 0 DEG C, fully stir, add ethyl acetate 650mL, filter, obtain clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and adjust pH=6.4, fully stir 1.5h, separate organic phase, drip dilute hydrochloric acid to pH=2.0 to aqueous phase, separate out white crystal, insulation growing the grain 30min, dry material, obtain cefoxitin 65.38g, yield 93.4%.
Embodiment 3
A preparation method for antibacterial drugs cefoxitin, comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
To in reaction vessel, add 7-ACA60g, be scattered in 350mL water, add the sodium hydroxide solution of 30%, pH value of solution is transferred to 8.4, control temperature is 4 DEG C of reactions that are hydrolyzed, molten clear rear continuation stirs 30min, add ethyl acetate 125mL, stir 15min, then drip dilute hydrochloric acid (1.2mol/L) and regulate pH=3.4, crystallize out, dry, obtain acetyl 7-amino-cephalosporanic acid 50.3g, yield 99.12%;
The preparation of compound ii
50.3g chemical compounds I is joined in the mixed solution of 360mL methylene dichloride and 36mL methyl alcohol, be cooled to-20 DEG C, stir 20min.Add methylsulfonic acid 2.099g, cool-55 DEG C, add NBS 59.22g in batches, add sodium methylate 294.84(401.45) g, abundant stirring 4h, every 0.5h sample high performance liquid chromatography detection compound I residual when being less than 1% reaction terminate, obtain containing compound ii mixed solution, be directly used in next step and react;
The preparation of compound III
Under rapid mixing conditions, in compound ii mixed solution, drip 2-thiophen acetyl chloride 40.19g, temperature controls at 6 DEG C, and 2.5h drips, then continue insulated and stirred 3h, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 7.5, drip purified water 150mL, solution turned cloudy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration, with the methylene dichloride of cooling and the mixed solution washing of methyl alcohol, dry material, obtain compound III 79.37g, yield 95.5%;
The synthesis of cefoxitin
70g compound III is dissolved in 300mL tetrahydrofuran (THF), stirs and be cooled to-45 DEG C, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to and fully react 1.5h.In reaction solution, add the purified water 180mL of 0 DEG C, fully stir, add ethyl acetate 650mL, filter, obtain clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and adjust pH=6, fully stir 1.5h, separate organic phase, drip dilute hydrochloric acid to pH=2.1 to aqueous phase, separate out white crystal, insulation growing the grain 30min, dry material, obtain cefoxitin 65.87g, yield 94.1%.
Embodiment 4
A preparation method for antibacterial drugs cefoxitin, comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
To in reaction vessel, add 7-ACA60g, be scattered in 350mL water, add the sodium hydroxide solution of 40%, pH value of solution is transferred to 8.4, control temperature is 3 DEG C of reactions that are hydrolyzed, molten clear rear continuation stirs 50min, adds ethyl acetate 125mL, stirs 15min, then the dilute hydrochloric acid of 1.2mol/L is dripped, regulate pH=2.5, crystallize out, dry, obtain acetyl 7-amino-cephalosporanic acid 49.8g, yield 98.14%;
The preparation of compound ii
49.8g chemical compounds I is joined in the mixed solution of 430mL methylene dichloride and 36mL methyl alcohol, be cooled to-21 DEG C, stir 20min.Add methylsulfonic acid 2.079g, cool-40 DEG C, add NBS 87.00g in batches, add sodium methylate 292.00g, fully stir 2h, every 0.5h sample high performance liquid chromatography detection compound I residual when being less than 1% reaction terminate, obtain containing compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under rapid mixing conditions, in compound ii mixed solution, drip 2-thiophen acetyl chloride 39.80g, temperature controls at 14 DEG C, and 2.5h drips, then continue insulated and stirred 3h, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 7.5, drip purified water 180mL, solution turned cloudy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration, with the methylene dichloride of cooling and the mixed solution washing of methyl alcohol, dry material, obtain compound III 79g, yield 96%;
The synthesis of cefoxitin
70g compound III is dissolved in 300mL tetrahydrofuran (THF), stirs and be cooled to-42 DEG C, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to and fully react 1.5h.In reaction solution, add the purified water 180mL of 0 DEG C, fully stir, add ethyl acetate 650mL, filter, obtain clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and adjust pH=6.6, fully stir 1.5h, separate organic phase, drip dilute hydrochloric acid to pH=1.5 to aqueous phase, separate out white crystal, insulation growing the grain 30min, dry material, obtain cefoxitin 64.96g, yield 92.8%.
Claims (1)
1. a preparation method for antibacterial drugs cefoxitin, is characterized in that, comprises the steps:
Go the preparation of acetyl 7-amino-cephalosporanic acid
To in reaction vessel, add 7-ACA60g, be scattered in 350mL water, add the sodium hydroxide solution of 30%, pH value of solution is transferred to 8.4, control temperature is 4 DEG C of reactions that are hydrolyzed, molten clear rear continuation stirs 30min, add ethyl acetate 125mL, stir 15min, then drip 1.2mol/L dilute hydrochloric acid and regulate pH=3.4, crystallize out, dry, obtain acetyl 7-amino-cephalosporanic acid 50.3g, yield 99.12%;
The preparation of compound ii
50.3g chemical compounds I is joined in the mixed solution of 360mL methylene dichloride and 36mL methyl alcohol, be cooled to-20 DEG C, stir 20min; Add methylsulfonic acid 2.099g, cool-55 DEG C, add NBS 59.22g in batches, add sodium methylate 294.84g, fully stir 4h, every 0.5h sample high performance liquid chromatography detection compound I residual when being less than 1% reaction terminate, obtain containing compound ii mixed solution, be directly used in next step reaction;
The preparation of compound III
Under rapid mixing conditions, in compound ii mixed solution, drip 2-thiophen acetyl chloride 40.19g, temperature controls at 6 DEG C, and 2.5h drips, then continue insulated and stirred 3h, add the sodium hydroxide solution of 20%, pH value of solution is transferred to 7.5, drip purified water 150mL, solution turned cloudy, growing the grain 30min; Continue to drip purified water 650mL, suction filtration, with the methylene dichloride of cooling and the mixed solution washing of methyl alcohol, dry material, obtain compound III 79.37g, yield 95.5%;
The synthesis of cefoxitin
70g compound III is dissolved in 300mL tetrahydrofuran (THF), stirs and be cooled to-45 DEG C, drip cold chloro sulfonyl isocyanate 58.5g, be stirred to and fully react 1.5h; In reaction solution, add the purified water 180mL of 0 DEG C, fully stir, add ethyl acetate 650mL, filter, obtain clear filtrate, add 10% sodium chloride solution 200mL, stir 30min, drip saturated sodium carbonate solution and adjust pH=6, fully stir 1.5h, separate organic phase, drip dilute hydrochloric acid to pH=2.1 to aqueous phase, separate out white crystal, insulation growing the grain 30min, dry material, obtain cefoxitin 65.87g, yield 94.1%.
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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 |
| CN108440568B (en) * | 2018-04-11 | 2019-04-02 | 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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