CN103265562A - Preparation method of cefixime - Google Patents
Preparation method of cefixime Download PDFInfo
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- CN103265562A CN103265562A CN2013102047347A CN201310204734A CN103265562A CN 103265562 A CN103265562 A CN 103265562A CN 2013102047347 A CN2013102047347 A CN 2013102047347A CN 201310204734 A CN201310204734 A CN 201310204734A CN 103265562 A CN103265562 A CN 103265562A
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Abstract
The invention discloses a preparation method of cefixime. The problems of bad stability, low yield and large material dissipation of products prepared by an existing preparation method of cefixime are solved. The preparation method disclosed by the invention comprises the following steps of: enabling 2-methoxycarbonylmethoxyimino-4-chloro-3-oxobutyric acid (CMOBA) to react with phosphorus oxychloride under the action of N,N-dimethylformamide (namely, DMF) to obtain acyl chloride; enabling 7-amino-3-vinyl-8-oxo-5-thio-1-azabicyclo[4.2.0] octyl-2-alkene-2-carboxylic acid (namely, 7-AVCA) to react with hexamethyldisilazane (namely, HMDS) under the action of acetamide, and protecting the 2-bit carboxyl and 7-bit amino of the 7AVCA by utilizing dichloromethane as a solvent; dripping the obtained acyl chloride into the dichloromethane solution protected by the 7AVCA to react, hydrolyzing, adding thiourea to react, adjusting pH to obtain cefixime ester (MECEF), hydrolyzing through sodium hydroxide, and adjusting pH to obtain cefixime. The cefixime prepared by using the preparation method disclosed by the invention is stable in quality, high in yield and low in cost, thereby being suitable for industrial production.
Description
Technical field:
The present invention is relevant with the preparation method of Cefixime Micronized.
Background technology:
The disclosed operational path of the preparation method of the Cefixime Micronized that has the sixth of the twelve Earthly Branches such as US20030208065A1 is as follows:
1.7AVCA with N, the two silica-based ethanamides of front three of O-cool off at room temperature reaction.
2.DMF be dissolved in tetrahydrofuran (THF), low temperature drips phosphorus oxychloride, the reaction certain hour adds CMOBA, the acyl chlorides of low-temp reaction certain hour system then.
3. acyl chlorides is added dropwise in 1 the reaction certain hour.
4. directly in 3, add thiourea solution, acid adjustment simultaneously, the room temperature reaction certain hour, and be acid with sodium bicarbonate aqueous solution maintenance solution simultaneously, tell organic phase, add methylene dichloride and methyl alcohol, acid adjustment then, tell organic phase again and concentrate and do, add the tert-Octylamine salify, filtration obtains.
5. the salt that obtains adds water, and cooling, adds alkali and makes its hydrolysis, adds the excessive alkali of acid neutralization then, and activated carbon decolorizing filters, and acid adjustment obtains Cefixime Micronized.Yield is 39.1%(actual recovery/theoretical yield).
Above-mentioned explained hereafter efficient is low, the cost height, and product yield is low, and active component content is low, unstable properties.
Summary of the invention:
The purpose of this invention is to provide a kind of production efficiency height, cost is low, product yield height, active component content height, the preparation method of the Cefixime Micronized of stable performance.
The present invention is achieved in that
The preparation method of Cefixime Micronized; adopt 2-methoxyl group formyl methoxyimino-4-chloro-3-ketobutyric acid CMOBA at N; dinethylformamide DMF effect is descended and phosphorus oxychloride reaction obtains acyl chlorides; 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 7-AVCA is under the ethanamide effect; react with hexamethyldisilazane HMDS; make solvent with methylene dichloride; 2 carboxyls and the protection of 7 bit aminos with 7AVCA; again the acyl chlorides that obtains is splashed in the dichloromethane solution of 7AVCA protection and react; hydrolysis again; add the thiocarbamide reaction again; acid adjustment obtains Cefixime Micronized methyl esters MECEF; through sodium hydroxide hydrolysis, acid adjustment obtains Cefixime Micronized.
The preparation method of Cefixime Micronized, step is as follows:
1. in there-necked flask, add 100-500 ml methylene dichloride, 8-12g7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 7AVCA, the 10-15g ethanamide, stir, add 25-30g hexamethyldisilazane HMDS again, backflow 1-5 hour, temperature 39-41 ℃, get intermediate (1);
2. in there-necked flask, add the 30-60ml methylene dichloride, 4-8gN, dinethylformamide DMF,-30-0 degree drips the 6-10g phosphorus oxychloride,-30-0 degree reaction 10-55 minute adds 12-15g2-methoxyl group formyl methoxyimino-4-chloro-3-ketobutyric acid CMOBA again ,-30-0 degree reaction 0.5-3 hour, the whole process nitrogen protection gets intermediate (2);
3. step intermediate (2) is added dropwise in the intermediate (1), the control temperature was reacted 0.5-3 hour at-30-0 ℃, and the control temperature is at-30-0 ℃, and nitrogen protection gets intermediate (3);
4. add the 50-200ml purified water in intermediate (3), stirred 10-20 minute, temperature is controlled at 30-40 ℃;
5. leave standstill 10-20 minute separatory, the water waste liquid barrel of packing into;
6. add the 100-200ml purified water in the organic phase, stir, with mass percentage concentration 5-10% sodium bicarbonate aqueous solution, regulate PH between the 5-7;
7. add the 8-10g thiocarbamide, reacted 1-3 hour, temperature of reaction is controlled PH5-7 at 20-30 ℃ in the reaction;
8. reaction finishes, and leaves standstill separatory, and organic phase reclaims barrelling; Aqueous phase adds disodium ethylene diamine tetraacetate 0.2-1g, and regulates between the PH to 2-4 with mass percentage concentration 5%-30% hydrochloric acid, and temperature, continues to stir 1-3 hour at 10-20 ℃ in control, and suction filtration obtains Cefixime Micronized methyl esters MECEF;
9. the MECEF that obtains is added in the there-necked flask, add the 100-600ml purified water again, stir, add the 50-300ml aqueous solution of 5-20g sodium hydroxide, temperature is controlled at 0-15 ℃, reacts 10-60 minute;
10. reaction finishes, and adds mass percentage concentration 2-20% hydrochloric acid and regulates between the PH to 5-7, is warming up to 10-25 ℃ of degree, adds disodium ethylene diamine tetraacetate 0.1-0.2g and gac 1-2g, stirs 15-45 minute;
11. suction filtration, the filtrate that obtains is regulated PH to 2-4 with the hydrochloric acid of mass percentage concentration 2-20%, and the control temperature continues to stir 1-3 hour at 0-20 ℃ of degree, suction filtration, and 30-60 ℃ of dry 2-6 of filter cake vacuum hour, obtain the Cefixime Micronized methyl esters,
12. Cefixime Micronized methyl esters MECEF is through sodium hydroxide hydrolysis, acid adjustment obtains Cefixime Micronized,
Its reaction formula is as follows:
The preparation method of Cefixime Micronized is:
In the described step 1, the part by weight of ethanamide and 7-AVCA is at 1.5:1～1:1, and the volume weight ratio of methylene dichloride and 7-AVCA is at 10V:1～50V:1, ml/g
In the described step 2, dropping temperature-20 is to-15 ℃; Temperature of reaction-20 is to-18 ℃;
In the described step 3, dropping, temperature of reaction are-18 to-12 ℃;
In the described step 6, PH5.5-5.75;
In the described step 8, PH3-3.5;
In the described step 10, PH5.5-5.8;
In the described step 11, temperature is controlled at 5-10 ℃; PH control is at 3-3.3.Selecting advantage like this is better to control side reaction, reduces impurity and produces, and improves yield, and product is more stable.
The preparation method of Cefixime Micronized is:
In the described step 1, the part by weight of ethanamide and 7-AVCA is at 1.5:1, and the volume weight ratio of methylene dichloride and 7-AVCA is at 20V:1, ml/g.
Advantage of the present invention is as follows:
1. substitute N, the two silica-based ethanamides of front three of O-are hexamethyldisilazane, and add the ethanamide temperature reaction, have accelerated speed of reaction, and the minimizing reaction times reaches same purpose, has improved production efficiency.
2. do not use these solvents of tetrahydrofuran (THF) and methyl alcohol, only used the single solvent methylene dichloride, be more conducive to the recovery of solvent.Improved production efficiency, provided cost savings.
3. simplified tert-Octylamine salify purification step, refiningly the same can obtain qualified finished product, and refiningly can reduce yield, thus simplify reactions steps, more quickly and effectively obtain qualified finished product, reduce material loss, improved production efficiency, provide cost savings.
4. finally obtaining Cefixime Micronized has increased the growing the grain process, makes product that crystal formation be arranged, and content is also had raising, and content is brought up to more than 98%.
5. adopt the chloride method of optimizing technology parameters to make Cefixime Micronized, better control side reaction, reduce impurity and produce, improve yield, product is more stable, has solved the problem of Cefixime Micronized poor stability, has promoted yield greatly.
Embodiment:
Percentage concentration is mass percentage concentration among the following embodiment.
Embodiment 1:
1. in there-necked flask, add 250 ml methylene dichloride, 10g7AVCA, the 13g ethanamide stirs, and adds 30gHMDS again, and 39 ℃ were refluxed 1.5 hours, and got intermediate 1.
2. in there-necked flask, add the 50ml methylene dichloride, 4gDMF ,-17 ℃ drip the 10g phosphorus oxychloride, dropwise in 15 minutes ,-19 ℃ of reactions 20 minutes, directly add 13gCMOBA again, and-19 ℃ were reacted 0.5 hour, and the whole process nitrogen protection gets intermediate 2.
3. intermediate 2 is added dropwise in the intermediate 1, dripped off in 30 minutes, the control temperature was-16 ℃ of reactions 1 hour, and 7AVCA＜1% is controlled in nitrogen protection among the liquid phase HPLC;
4. reaction finishes, and adds the 50ml purified water, stirs 10 minutes, and temperature is controlled at 34 ℃;
5. leave standstill 10 minutes separatory, the water waste liquid barrel of packing into;
6. add the 100ml purified water in the organic phase, stir, use 10% sodium bicarbonate aqueous solution, regulate PH to 5.8;
7. add the 8g thiocarbamide, reacted 1 hour, temperature of reaction is at 23 ℃, and reaction is controlled PH6 up to the constant no change of PH with 10% sodium bicarbonate aqueous solution;
8. reaction finishes, and leaves standstill separatory, and organic phase reclaims barrelling; Aqueous phase adds disodium ethylene diamine tetraacetate 0.2g, and regulates PH to 3.1 with 10% hydrochloric acid, and temperature is controlled at 11 ℃, continues to stir 1 hour, and suction filtration obtains the wet product 48g of MECEF;
9. the MECEF that obtains is added in the there-necked flask, add the 100ml purified water again, stir, add the 100ml aqueous solution of 5g sodium hydroxide, temperature is controlled at 11 ℃, reaction 15min, control Cefixime Micronized methyl esters＜1% among the liquid phase HPLC;
10. reaction finishes, and adds 10% hydrochloric acid and regulates PH to 6, is warming up to 20 ℃, adds disodium ethylene diamine tetraacetate 0.1g and gac 2g, stirs 15 minutes;
11. suction filtration, the filtrate that obtains, the hydrochloric acid with 10% is adjusted to muddiness, and growing the grain 30min continues to regulate PH to 3.2 with 10% hydrochloric acid more then, and the control temperature continues to stir 1 hour at 16 ℃, suction filtration, dry 6 hours of filter cake vacuum 45 degree obtain Cefixime Micronized 18.8g.Yield is 83.8%.
Embodiment 2:
1. in there-necked flask, add 250 ml methylene dichloride, 10g7AVCA, the 10g ethanamide stirs, and adds 25gHMDS again, and 40 ℃ were refluxed 3 hours; Get intermediate 1.
2. in there-necked flask, add the 50ml methylene dichloride, 5.5gDMF ,-13 ℃ drip the 9g phosphorus oxychloride, dropwise in 20 minutes ,-18 ℃ of reactions 40 minutes, directly add 12.5gCMOBA again, and-12 ℃ were reacted the whole process nitrogen protection 1 hour; Get intermediate 2.
3. intermediate 2 is added dropwise in the intermediate 1, dripped off in 35 minutes, the control temperature was-12 ℃ of reactions 1.5 hours, and 7AVCA＜1% is controlled in nitrogen protection among the liquid phase HPLC;
4. reaction finishes, and adds the 50ml purified water, stirs 15 minutes, and temperature is controlled at 35 ℃;
5. leave standstill 15 minutes separatory, the water waste liquid barrel of packing into;
6. add the 150ml purified water in the organic phase, stir, use 8% sodium bicarbonate aqueous solution, regulate PH to 5.6;
7. add the 8g thiocarbamide, reacted 1 hour, temperature of reaction is controlled PH6 up to PH constant no change with 8% sodium bicarbonate aqueous solution at 27 ℃ in the reaction;
8. reaction finishes, and leaves standstill separatory, and organic phase reclaims barrelling; Aqueous phase adds disodium ethylene diamine tetraacetate 0.2g, and regulates PH to 2.8 with 5% hydrochloric acid, and temperature is controlled at 12 ℃, continues to stir 1 hour, and suction filtration obtains the wet product 48g of MECEF;
9. the MECEF that obtains is added in the there-necked flask, add the 100ml purified water again, stir, add the 100ml aqueous solution of 6g sodium hydroxide, temperature is controlled at 12 ℃, reaction 15min, control Cefixime Micronized methyl esters＜1% among the liquid phase HPLC;
10. reaction finishes, and adds 10% hydrochloric acid and regulates PH to 5.6, is warming up to 20 ℃, adds disodium ethylene diamine tetraacetate 0.1g and gac 2g, stirs 15 minutes;
11. suction filtration, the filtrate that obtains, the hydrochloric acid with 10% is adjusted to muddiness, and growing the grain 30min continues to regulate PH to 3 with 10% hydrochloric acid then, and the control temperature continues to stir 1 hour at 17 ℃, suction filtration, 45 ℃ of dryings of filter cake vacuum 6 hours obtain Cefixime Micronized 15.2g.Yield is 67.8%.
Claims (4)
1. the preparation method of Cefixime Micronized; it is characterized in that adopting 2-methoxyl group formyl methoxyimino-4-chloro-3-ketobutyric acid CMOBA at N; dinethylformamide DMF effect is descended and phosphorus oxychloride reaction obtains acyl chlorides; 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 7-AVCA is under the ethanamide effect; react with hexamethyldisilazane HMDS; make solvent with methylene dichloride; 2 carboxyls and the protection of 7 bit aminos with 7AVCA; again the acyl chlorides that obtains is splashed in the dichloromethane solution of 7AVCA protection and react; hydrolysis again; add the thiocarbamide reaction again; acid adjustment obtains Cefixime Micronized methyl esters MECEF; through sodium hydroxide hydrolysis, acid adjustment obtains Cefixime Micronized.
2. the preparation method of Cefixime Micronized according to claim 1 is characterized in that, step is as follows:
1) in there-necked flask, adds 100-500 ml methylene dichloride, 8-12g7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 7AVCA, the 10-15g ethanamide, stir, add 25-30g hexamethyldisilazane HMDS again, backflow 1-5 hour, temperature 39-41 ℃, get intermediate (1);
2) in there-necked flask, add the 30-60ml methylene dichloride, 4-8gN, dinethylformamide DMF,-30-0 degree drips the 6-10g phosphorus oxychloride,-30-0 degree reaction 10-55 minute adds 12-15g2-methoxyl group formyl methoxyimino-4-chloro-3-ketobutyric acid CMOBA again ,-30-0 degree reaction 0.5-3 hour, the whole process nitrogen protection gets intermediate (2);
3) step intermediate (2) is added dropwise in the intermediate (1), the control temperature was reacted 0.5-3 hour at-30-0 ℃, and the control temperature is at-30-0 ℃, and nitrogen protection gets intermediate (3);
4) add the 50-200ml purified water in intermediate (3), stirred 10-20 minute, temperature is controlled at 30-40 ℃;
5) leave standstill 10-20 minute separatory, the water waste liquid barrel of packing into;
6) add the 100-200ml purified water in the organic phase, stir, with mass percentage concentration 5-10% sodium bicarbonate aqueous solution, regulate PH between the 5-7;
7) add the 8-10g thiocarbamide, reacted 1-3 hour, temperature of reaction is controlled PH5-7 at 20-30 ℃ in the reaction;
8) reaction finishes, and leaves standstill separatory, and organic phase reclaims barrelling; Aqueous phase adds disodium ethylene diamine tetraacetate 0.2-1g, and regulates between the PH to 2-4 with mass percentage concentration 5%-30% hydrochloric acid, and temperature, continues to stir 1-3 hour at 10-20 ℃ in control, and suction filtration obtains Cefixime Micronized methyl esters MECEF;
9) MECEF that obtains is added in the there-necked flask, add the 100-600ml purified water again, stir, add the 50-300ml aqueous solution of 5-20g sodium hydroxide, temperature is controlled at 0-15 ℃, reacts 10-60 minute;
10) reaction finishes, and adds mass percentage concentration 2-20% hydrochloric acid and regulates between the PH to 5-7, is warming up to 10-25 ℃ of degree, adds disodium ethylene diamine tetraacetate 0.1-0.2g and gac 1-2g, stirs 15-45 minute;
11) suction filtration, the filtrate that obtains is regulated PH to 2-4 with the hydrochloric acid of mass percentage concentration 2-20%, and the control temperature continues to stir 1-3 hour at 0-20 ℃ of degree, suction filtration, 30-60 ℃ of dry 2-6 of filter cake vacuum hour, obtain the Cefixime Micronized methyl esters,
12) Cefixime Micronized methyl esters MECEF is through sodium hydroxide hydrolysis, and acid adjustment obtains Cefixime Micronized.
3. the preparation method of Cefixime Micronized according to claim 2 is characterized in that in the described step 1), and the part by weight of ethanamide and 7-AVCA is at 1.5:1～1:1, and the volume weight ratio of methylene dichloride and 7-AVCA is at 10V:1～50V:1, ml/g,
Described step 2) in, dropping temperature-20 is to-15 ℃; Temperature of reaction-20 is to-18 ℃;
In the described step 3), dropping, temperature of reaction are-18 to-12 ℃;
In the described step 6), PH5.5-5.75;
In the described step 8), PH3-3.5;
In the described step 10), PH5.5-5.8;
In the described step 11), temperature is controlled at 5-10 ℃; PH control is at 3-3.3.
4. the preparation method of Cefixime Micronized according to claim 3 is characterized in that in the described step 1), and the part by weight of ethanamide and 7-AVCA is at 1.5:1, and the volume weight ratio of methylene dichloride and 7-AVCA is at 20V:1, ml/g.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232305A (en) * | 2018-08-28 | 2019-01-18 | 山东金城柯瑞化学有限公司 | The preparation method of CMOBA |
| CN111171051A (en) * | 2020-03-05 | 2020-05-19 | 张炳哲 | Preparation method of cefixime |
| CN111606925A (en) * | 2020-07-01 | 2020-09-01 | 心邀（深圳）生物科技有限公司 | Preparation method of cefixime delta 3 isomer impurity |
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| US4283396A (en) * | 1976-01-23 | 1981-08-11 | Roussel Uclaf | 3-Acetoxymethyl-7-(hydroxyiminoacetamido)-cephalosporanic acid derivatives |
| CN1295576A (en) * | 1998-04-02 | 2001-05-16 | 生物化学有限公司 | Process for purification of cephalosporin derivative |
| WO2004058695A1 (en) * | 2002-12-26 | 2004-07-15 | Lupin Limited | Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates |
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
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2013
- 2013-05-29 CN CN2013102047347A patent/CN103265562A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4283396A (en) * | 1976-01-23 | 1981-08-11 | Roussel Uclaf | 3-Acetoxymethyl-7-(hydroxyiminoacetamido)-cephalosporanic acid derivatives |
| CN1295576A (en) * | 1998-04-02 | 2001-05-16 | 生物化学有限公司 | Process for purification of cephalosporin derivative |
| WO2004058695A1 (en) * | 2002-12-26 | 2004-07-15 | Lupin Limited | Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates |
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
Non-Patent Citations (1)
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| 胡艾希 等: "头孢克肟的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232305A (en) * | 2018-08-28 | 2019-01-18 | 山东金城柯瑞化学有限公司 | The preparation method of CMOBA |
| CN111171051A (en) * | 2020-03-05 | 2020-05-19 | 张炳哲 | Preparation method of cefixime |
| CN111606925A (en) * | 2020-07-01 | 2020-09-01 | 心邀（深圳）生物科技有限公司 | Preparation method of cefixime delta 3 isomer impurity |
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