CN102093390B - Method for preparing cefuroxime acid - Google Patents
Method for preparing cefuroxime acid Download PDFInfo
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- CN102093390B CN102093390B CN201110030084XA CN201110030084A CN102093390B CN 102093390 B CN102093390 B CN 102093390B CN 201110030084X A CN201110030084X A CN 201110030084XA CN 201110030084 A CN201110030084 A CN 201110030084A CN 102093390 B CN102093390 B CN 102093390B
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- 0 *C1=C(C(O)=O)N*SC1 Chemical compound *C1=C(C(O)=O)N*SC1 0.000 description 3
- YOUHCFQQMRZNJJ-UHFFFAOYSA-N CC(C1SCC(CO)=C(C(O)=O)N11)C1=O Chemical compound CC(C1SCC(CO)=C(C(O)=O)N11)C1=O YOUHCFQQMRZNJJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a method for preparing cefuroxime acid. The method comprises the following steps: (1) selectively hydrolyzing 7-aminocephalosporanic acid (7-ACA) with aqueous alkali so as to obtain 3-deacetylation-7-aminocephalosporanic acid (7-DACA); (2) condensing 2-(2-furyl)-2-(methoxyimino)acetic acid-(2,5-dioxo-pyrrolidyl)-1-ester and 7-DACA so as to obtain 3-decarbamyl-cefuroxime acid (DCCF); and (3) modifying 3-hydroxymethyl of DCCF with chlorosulfonyl isocyanate so as to obtain the cefuroxime acid. In the method, low-temperature selective hydrolysis is carried out by using inorganic base to remove the 3-ester group of 7-ACA so as to prepare 7-DACA; C7-amino modification is carried out by an active ester method so as to obtain DCCF; and the 3-hydroxymethyl of DCCF is modified into carbamoyl methoxyl so as to obtain the cefuroxime acid. The method has the advantages of less emission of three wastes and high yield, is simple and convenient to operate, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method for preparing cefuroxime acid, belong to the synthetic field of medicine.
Background technology
Cephalofruxin series genus the 2nd generation cynnematin; Has broad-spectrum antibacterial action; Not only gram-positive cocci there is stronger anti-microbial activity; And also have excellent antibiotic active to some gram negative bacterium, especially in the treatment of Gram-positive and gram negative bacterium polyinfection, preferentially select this medicine especially for use.It produces the pharmaceutically-active lytic enzyme of destruction to bacterium and has high stability, few generation untoward reaction in clinical application.
Cephalofruxin is succeeded in developing by Glaxo Wellcome company at first and is patented.This product at first went on the market in Britain, Ireland, Germany and Italy in 1978, and commodity are called " zinacef ", and sell many countries and regions in the whole world subsequently.On December 28th, 1987 examined through U.S. FDA, went on the market in the U.S. in 1988.In early 1990s, this medicine has become world's situation of selling well anti-infectives.At present, recorded by multinational pharmacopeia and China version pharmacopeia in 2000 such as English, U.S.A, days.
Cefuroxime acid (Cefuroxime acid); I.e. (6R; 7R)-7-[[2-furyl (suitable-methoxyimino) ethanoyl] amino]-3-carbamyl yloxymethyl cephalo-3-alkene-4-carboxylic acid; It is the important intermediate of products such as synthetic cephalofruxin, cefuroxime axetil, Cefuroxime sodium, has reported many synthetic routes at present, and the main technique route is:
1, be raw material with 7-amino-cephalosporanic acid (7-ACA) and methoxy imino furans acetyl ammonium (SMIA); Earlier in systems such as methylene dichloride or ethylene dichloride, SMIA is made acyl chlorides; Then with the dissolving after 7-ACA carry out the N-acylation reaction; Under the strong basicity environment, 3 ethanoyl hydrolysis is fallen again, separated out 3-deammoniation formyl radical-cefuroxime acid at aqueous phase with the salt acid crystal at last, again the hydroxyl of 3-position is transformed into carboxamide oxygen methyl and obtains cefuroxime acid.
This method production cost is higher, participates in reaction because of acyl chlorides is arranged, and impurity is more in the product, and purity is low, is difficult for reaching medicinal requirements.Directly carry out the method for N-acylation reaction though develop subsequently, improve DeGrain with methoxy imino furans acetyl ammonium.
2,7-ACA is made key intermediate 3-deacetylation-7-amino-Cephalosporanic acid (7-DACA) through 3 ester groups of selective hydrolysis, obtain cefuroxime acid through two approach then.
Article one, after first 3 methylols with 7-DACA of approach transform carboxamide oxygen methyl as; Introduce cis-2-(2-furyl)-2-(methoxyimino) acetate at 7 bit aminos again and obtain cefuroxime acid; The shortcoming of this approach be transform 7-DACA with isocyanic ester 3 methylols simultaneously with the 7 bit aminos reaction of 7-DACA; Cause the yield of product lower, generally do not adopt this route now.
The second approach be with 7-DACA 7 for amino cis-2-(2-furyl)-2-(methoxyimino) acetate of introducing obtains 3-deammoniation formyl radical-cefuroxime acid, transform 3 methylols of 3-deammoniation formyl radical-cefuroxime acid as carboxamide oxygen methyl again and make cefuroxime acid.Improve perfectly through studying intensively of domestic colleague, this route has reached higher level.But this approach generally all is to adopt chloride method to introduce (cis)-2-(2-furyl)-2-(methoxyimino) acetate (SMIFA) in the C7-position of 7-DACA, is to a certain degree limiting its suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing cefuroxime acid, this technological operation is simple, three waste discharge is few, yield is high, is suitable for suitability for industrialized production.
In order to realize the object of the invention, preparing cefuroxime acid of the present invention, it comprises the steps:
(1) 7-amino-cephalosporanic acid (7-ACA) is obtained 3-deacetylation-7-amino-Cephalosporanic acid (7-DACA) with the alkaline solution selective hydrolysis;
(2) obtain 3-deammoniation formyl radical-cefuroxime acid (DCCF) with 2-(2-furyl)-2-(methoxyimino) acetate-(2,5-dioxo-pyrrolidyl)-1-ester and 7-DACA condensation;
(3) methylol with 3 of Sulfuryl chloride isocyanate transformation 3-deammoniation formyl radical-cefuroxime acids obtains cefuroxime acid.
Wherein, step (1) is: organic solvent is mixed as mixed solvent with water, add 7-ACA then, make its dissolving, be cooled to-15～0 ℃; Adding concentration expressed in percentage by weight is the alkaline solution of 5-30%, and control pH is 11～12, temperature is carried out selective hydrolysis under-15～0 ℃ the condition; After hydrolysis is accomplished, regulate pH to 7～8, obtain 7-DACA.
Wherein, said organic solvent is one or more in methyl alcohol, ethanol or the Virahol, is preferably methyl alcohol; Said alkaline solution is the aqueous solution of sodium hydroxide, Pottasium Hydroxide, and the perhaps mixing solutions of sodium hydroxide and Pottasium Hydroxide is preferably the aqueous solution of sodium hydroxide.In the mixed solvent, the volume ratio of said organic solvent and water 1: 0.5～1.5; The weight ratio of 7-amino-cephalosporanic acid and organic solvent is 1: 4～6.
Step (2) is: in the 7-DACA that step (1) makes, add triethylamine (Et
3N), add 2-(2-furyl)-2-(methoxyimino) acetate-(2,5-dioxo-pyrrolidyl)-1-ester then, ice-water bath is reaction down; Regulate pH to 2～3 after reaction is accomplished, acidizing crystal, filtration, vacuum-drying obtain DCCF.
Wherein, the weight ratio of 7-DACA and triethylamine is 1: 1～10, be preferably 1: 1.5～and 3.The weight ratio of 7-DACA and 2-(2-furyl)-2-(methoxyimino) acetate-(2,5-dioxo-pyrrolidyl)-1-ester is 1: 1～5, be preferably 1: 1.2～and 2; The temperature of said ice-water bath is 0～5 ℃.
Step (3) is: the DCCF that step (2) is made is dissolved in THF, adds Sulfuryl chloride isocyanate, and reaction 0.5h under-20～0 ℃ low temperature adds ice cube then and continues reaction; After reaction is accomplished, regulate pH to 6.5, with the ETHYLE ACETATE washing, pH to 2～2.5 are regulated in water intaking mutually then, and acidizing crystal, filtration, vacuum-drying obtain cefuroxime acid.
The mol ratio of said 3-deammoniation formyl radical-cefuroxime acid and Sulfuryl chloride isocyanate is 1: 1～5; The weight ratio of 3-deammoniation formyl radical-cefuroxime acid and ice cube is 1: 1～2.
Specifically, preparing cefuroxime acid of the present invention, it comprises the steps:
(1) organic solvent is mixed as mixed solvent with water 1: 0.5 by volume～1.5, add the 7-amino-cephalosporanic acid mixed dissolution, be cooled to-15～0 ℃ according to the ratio of the weight ratio 1: 4～6 of 7-amino-cephalosporanic acid and organic solvent; Add concentration expressed in percentage by weight and be 5～30% alkali aqueous solution, control pH is 11～12, temperature is carried out selective hydrolysis for-15～0 ℃, and it is reaction end that HPLC detects 7-ACA peak completely dissolve, about 1 hour of reaction times; After hydrolysis is accomplished, regulate pH to 7～8, obtain 7-DACA;
Said organic solvent is one or more in methyl alcohol, ethanol or the Virahol, is preferably methyl alcohol; Said alkali aqueous solution is the aqueous solution of sodium hydroxide, Pottasium Hydroxide, and the perhaps mixing solutions of sodium hydroxide and Pottasium Hydroxide is preferably the aqueous solution of sodium hydroxide;
(2) in the 7-DACA that step (1) makes, drip 1～10 times, the Et of preferred 1.5～3 times of 7-DACA weight
3N adds 1～5 times, 2-[2-furyl]-2-[methoxyimino] acetate-(2,5-dioxo-pyrrolidyl)-1-ester of preferred 1.2～2 times of 7-DACA weight then; Ice-water bath (0～5 ℃) is reaction down, and it is reaction end that HPLC detects 7-DACA revolution mark＜1%; Regulate pH to 2～3 after reaction is accomplished, acidizing crystal, filtration, vacuum-drying obtain DCCF;
(3) DCCF that step (2) is made is dissolved in THF, and 1: 1 in molar ratio～5 add Sulfuryl chloride isocyanate, under-20～0 ℃ low temperature, reacts 0.5h, adds the ice cube of 1～2 times of 3-deammoniation formyl radical-cefuroxime acid weight then, continues reaction; After treating that the ice dissolving finishes, regulate pH to 6.5, with the ETHYLE ACETATE washing, pH to 2～2.5 are regulated in water intaking mutually then, and acidizing crystal, filtration, vacuum-drying obtain cefuroxime acid.
The invention has the advantages that 3 ester groups that preparation method of the present invention adopts the hydrolysis of mineral alkali cryogenic selective to slough 7-ACA prepare 7-DACA, carry out C with active ester method then
7-amino preparation the DCCF that transforms transform 3 methylols of DCCF as carboxamide oxygen methyl again and makes cefuroxime acid, and this method technological operation is easy, three waste discharge is few, and yield is high, and is suitable for suitability for industrialized production.
Embodiment
Below further specify the present invention through specific embodiment, but be not used for limiting scope of the present invention.
Embodiment 1
Adding 550ml methyl alcohol, 550ml purified water are mixed into mixed solvent in reaction flask; Add 100g 7-ACA then, stir and cool to-15 ℃, drip 15% sodium hydroxide purification of aqueous solutions; Controlled temperature carries out the selective hydrolysis reaction under-15 ℃, the condition of pH 11～12; It is reaction end that HPLC detects 7-ACA peak completely dissolve, about 1 hour of reaction times; After reaction is accomplished, drip 2mol/L hydrochloric acid and regulate pH to 7.0～8.0, it is for use to obtain 7-DACA solution low temperature;
In above-mentioned 7-DACA solution, add 80ml Et
3N, 118.4g 2-[2-furyl]-2-[methoxyimino] acetate-(2,5-dioxo-pyrrolidyl)-1-ester react under the ice-water bath condition, and it is reaction end that HPLC detects 7-DACA revolution mark＜1%; Reaction is told water after accomplishing, and adds the 6g gac and stirs the half a hour of decolouring; Warp filters, washes then, cools to 5 ℃, drips 2mol/L hydrochloric acid to pH=2, and insulated and stirred 2 hours is filtered, and the dry 115g DCCF of getting of final vacuum is drained in the cryogenic purincation water washing, and yield is 82.2%.
30g DCCF is dissolved in 100ml THF, under-15 ℃ temperature, drips 9.5mlClSO
2NCO is dissolved in the solution behind the 40ml THF, and stirring reaction 0.5h under-15 ℃ temperature adds the 40g ice cube then, continues reaction; After treating that the ice dissolving finishes, drip saturated sodium bicarbonate solution, use ETHYLE ACETATE (EA) washing (3 times * 30ml/ time) then to pH=6.5; Keep water, add small amount of activated agitation and filtration, washing, the merging filtrate washing lotion; Drip 2mol/L hydrochloric acid to just separating out crystallization, stop to add acid, stir the 0.5h continued add hydrochloric acid to pH be 2.0～2.5; Ice bath is cooled to below 5 ℃, leaches crystal behind the 0.5h, the frozen water washed twice; The air-dry low-temperature vacuum drying again of room temperature gets the 29.1g cefuroxime acid to constant weight, and yield is 87.2%.Specific optical rotation :+63 °～+ 67 °; Fusing point: 172～173 ℃.
Embodiment 2
Adding 300ml ethanol, 300ml methyl alcohol, 600ml purified water are mixed into mixed solvent in reaction flask, add 100g 7-ACA then, stir and cool to 0 ℃; Drip 15% Pottasium Hydroxide purification of aqueous solutions; Controlled temperature is 0 ℃, and pH is 11～12, carries out the selective hydrolysis reaction; It is reaction end that HPLC detects 7-ACA peak completely dissolve, about 1 hour of reaction times; After reaction is accomplished, drip 2mol/L hydrochloric acid and regulate pH to 7.0～8.0, it is for use to obtain 7-DACA solution low temperature;
In above-mentioned 7-DACA solution, add 100ml Et
3N, 146.5g 2-[2-furyl]-2-[methoxyimino] acetate-(2,5-dioxo-pyrrolidyl)-1-ester react under the ice-water bath condition, and it is reaction end that HPLC detects 7-DACA revolution mark＜1%; Reaction is told water after accomplishing, and adds the 6g gac and stirs the half a hour of decolouring; Warp filters, washes then, cools to 5 ℃, and the hydrochloric acid that drips 2mol/L is to pH=2, and insulated and stirred 2 hours is filtered, and the cryogenic purincation water washing is drained the dry 120g DCCF of getting of final vacuum, yield 85.7%.
30g DCCF is dissolved in 110ml THF, under-20 ℃ temperature, drips 10mlClSO
2NCO is dissolved in the solution behind the THF 40ml, and stirring reaction 0.5h under-20 ℃ temperature adds the 50g ice cube then and continues reaction; After treating that the ice dissolving finishes, drip saturated sodium bicarbonate solution,, keep water then with EA washing (3 times * 30ml/ time) to pH=6.5; Add the small amount of activated agitation and filtration, washing, the merging filtrate washing lotion drips 2mol/L hydrochloric acid to just separating out crystallization; Stop to add acid, it is 2.0～2.5 to pH that stirring 0.5h continued adds hydrochloric acid, and ice bath is cooled to below 5 ℃, leaches crystal behind the 0.5h; Frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature get the 29.6g cefuroxime acid, yield 88.7% to constant weight.Specific optical rotation :+63 °～+ 67 °; Fusing point: 172～173 ℃.
Embodiment 3
Adding 600ml Virahol, 600ml purified water are mixed into mixing solutions in reaction flask; Add 100g 7-ACA then, stir and cool to-15 ℃, drip 30% sodium hydroxide purification of aqueous solutions; Controlled temperature is 11～12 at-15 ℃, pH value, carries out the selective hydrolysis reaction; It is reaction end that HPLC detects 7-ACA peak completely dissolve, about 1 hour of reaction times; After reaction is accomplished, drip 2mol/L hydrochloric acid and regulate pH to 7.0～8.0, it is for use to obtain 7-DACA solution low temperature;
In above-mentioned 7-DACA solution, add 110ml Et
3N, 160.5g 2-[2-furyl]-2-[methoxyimino] acetate-(2,5-dioxo-pyrrolidyl)-1-ester react under the ice-water bath condition, and it is reaction end that HPLC detects 7-DACA revolution mark＜1%; Reaction is told water after accomplishing, and adds the 6g gac and stirs the half a hour of decolouring; Warp filters, washes then, cools to 5 ℃, drips 2mol/L hydrochloric acid to pH=2, and insulated and stirred 2 hours is filtered, and the cryogenic purincation water washing is drained the dry 110g DCCF of getting of final vacuum, yield 78.6%.
30g DCCF is dissolved in 120ml THF, under-15 ℃ temperature, drips 9.2mlClSO
2NCO is dissolved in the solution of THF 30ml, and stirring reaction 0.5h under-15 ℃ temperature adds the 50g ice cube then, continues reaction; After treating that the ice dissolving finishes, drip saturated sodium bicarbonate solution,, keep water then with EA washing (3 times * 30ml/ time) to pH=6.5; Add the small amount of activated agitation and filtration, washing, the merging filtrate washing lotion drips 2mol/L hydrochloric acid to just separating out crystallization; Stop to add acid, it is 2.0～2.5 to pH that stirring 0.5h continued adds hydrochloric acid, and ice bath is cooled to below 5 ℃, leaches crystal behind the 0.5h; Frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature get the 28.3g cefuroxime acid, yield 84.8% to constant weight.Specific optical rotation :+63 °～+ 67 °; Fusing point: 172～173 ℃.
Though; With general explanation and specific embodiments, the present invention has been done detailed description in the preceding text, but on basis of the present invention; Can to some modifications of do or improvement; For example, can cefuroxime acid further be made commercially available prod Cefuroxime sodium or cefuroxime axetil etc. through methods such as esterifications, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (10)
1. method for preparing cefuroxime acid, it comprises the steps:
(1) 7-amino-cephalosporanic acid is obtained 3-deacetylation-7-amino-Cephalosporanic acid with the alkaline solution selective hydrolysis;
(2) in 3-deacetylation-7-amino-Cephalosporanic acid that step (1) makes, add triethylamine, add 2-[2-furyl]-2-[methoxyimino] acetate-(2,5-dioxo-pyrrolidyl)-1-ester then, ice-water bath is reaction down; Regulate pH to 2～3 after reaction is accomplished, acidizing crystal, filtration, vacuum-drying obtain 3-deammoniation formyl radical-cefuroxime acid;
(3) methylol with 3 of Sulfuryl chloride isocyanate transformation 3-deammoniation formyl radical-cefuroxime acids obtains cefuroxime acid.
2. method according to claim 1 is characterized in that, step (1) is: organic solvent is mixed as mixed solvent with water, add 7-amino-cephalosporanic acid then, make its dissolving, be cooled to-15～0 ℃; The adding concentration expressed in percentage by weight is 5～30% alkaline solution, and control pH is 11～12, carries out selective hydrolysis in temperature under-15～0 ℃ the condition; After hydrolysis is accomplished, regulate pH to 7～8, obtain 3-deacetylation-7-amino-Cephalosporanic acid.
3. method according to claim 2 is characterized in that, said organic solvent is one or more in methyl alcohol, ethanol or the Virahol; Said alkaline solution is the aqueous solution of sodium hydroxide, Pottasium Hydroxide, perhaps the mixing solutions of sodium hydroxide and Pottasium Hydroxide.
4. according to claim 2 or 3 described methods, it is characterized in that, in the mixed solvent, the volume ratio of said organic solvent and water 1: 0.5～1.5; The weight ratio of 7-amino-cephalosporanic acid and organic solvent is 1: 4～6.
5. method according to claim 1 is characterized in that, the weight ratio of 3-deacetylation-7-amino-Cephalosporanic acid and triethylamine is 1: 1～10.
6. method according to claim 5 is characterized in that, the weight ratio of 3-deacetylation-7-amino-Cephalosporanic acid and triethylamine is 1: 1.5～3.
7. method according to claim 1 is characterized in that, the weight ratio of 3-deacetylation-7-amino-Cephalosporanic acid and 2-(2-furyl)-2-(methoxyimino) acetate-(2,5-dioxo-pyrrolidyl)-1-ester is 1: 1～5.
8. method according to claim 7 is characterized in that, the weight ratio of 3-deacetylation-7-amino-Cephalosporanic acid and 2-(2-furyl)-2-(methoxyimino) acetate-(2,5-dioxo-pyrrolidyl)-1-ester is 1: 1.2～2.
9. method according to claim 1 is characterized in that, step (3) is: 3-deammoniation formyl radical-cefuroxime acid that step (2) is made is dissolved in THF; Add Sulfuryl chloride isocyanate; Reaction 0.5h adds ice cube then under-20～0 ℃ low temperature, continues reaction; After reaction is accomplished, regulate pH to 6.5, with the ETHYLE ACETATE washing, pH to 2～2.5 are regulated in water intaking mutually then, and acidizing crystal, filtration, vacuum-drying obtain cefuroxime acid.
10. method according to claim 9 is characterized in that, the mol ratio of said 3-deammoniation formyl radical-cefuroxime acid and Sulfuryl chloride isocyanate is 1: 1～5; The weight ratio of 3-deammoniation formyl radical-cefuroxime acid and ice cube is 1: 1～2.
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| CN102746323B (en) * | 2012-06-26 | 2014-05-07 | 天津大学 | Crystal form of cefuroxime acid and preparation method thereof |
| CN104072516A (en) * | 2014-06-18 | 2014-10-01 | 珠海保税区丽珠合成制药有限公司 | Method for synthesizing cefuroxime acid |
| CN109456339A (en) * | 2018-09-27 | 2019-03-12 | 湖北凌晟药业有限公司 | A kind of synthetic method of Cefuroxime Sodium |
| CN112679525B (en) * | 2020-12-24 | 2022-09-30 | 齐鲁安替制药有限公司 | Preparation method of cefuroxime acid |
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| WO2000071547A1 (en) * | 1999-05-21 | 2000-11-30 | Antibioticos S.P.A. | A PROCESS FOR THE PREPARATION OF β-LACTAM DERIVATIVES |
| CN101054386A (en) * | 2006-11-12 | 2007-10-17 | 西南合成制药股份有限公司 | Method of synthesizing cefuroxime |
| CN101289456A (en) * | 2008-06-07 | 2008-10-22 | 沂源鑫泉化工有限公司 | Method for synthesizing cefuroxime sodium |
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| WO2000071547A1 (en) * | 1999-05-21 | 2000-11-30 | Antibioticos S.P.A. | A PROCESS FOR THE PREPARATION OF β-LACTAM DERIVATIVES |
| CN101054386A (en) * | 2006-11-12 | 2007-10-17 | 西南合成制药股份有限公司 | Method of synthesizing cefuroxime |
| CN101289456A (en) * | 2008-06-07 | 2008-10-22 | 沂源鑫泉化工有限公司 | Method for synthesizing cefuroxime sodium |
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