CN102816173B - Preparation method of cefodizime sodium - Google Patents

Abstract

The invention relates to a preparation method of cefodizime sodium. By the preparation method, GCLE substitutes for traditional 7-ACA (7-Aminocephalosporanic acid) as starting materials to synthesize the cefodizime sodium, and after decoloration, reaction liquor is not subjected to separation and purification but is directly dropwise added with salt-forming agents for reaction so that the cefodizime sodium is obtained. The preparation method is short in step and less in side reaction, solves the problem of high superpolymer content of a final product and enables the superpolymer content to be decreased from 1.0% to smaller than 0.1%, product purity is improved and is above 99.8%, and product yield is improved and is above 90% by the aid of the raw material ratio and mixed solvent. Additionally, the preparation method is shorter in process step, timesaving, simple in process, high in yield and product purity, low in cost, cheap and available in raw materials and suitable for industrial production.

Description

A kind of preparation method of cefodizime sodium

technical field

The invention belongs to the field of chemical drug synthesis, and in particular relates to a method for preparing cefodizime sodium by using GCLE as a starting material.

Background technique

Cefodizime sodium, also known as cefodizime, the English name is Cefodizime Sodium, and its chemical name is: (6R,7R)-7-[(2-amino-4-thiazolyl)-(methoxyimino)acetamide Base]-3-[[(5-carboxymethyl-4-methyl-2-thiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] Oct-2-ene-2-carboxylic acid disodium salt, molecular formula: C ₂₀ H ₁₈ N ₆ O ₇ S ₄ Na ₂ , molecular weight: 628.64, structural formula as shown in compound V:

Cefodizime sodium belongs to the third generation of cephalosporin antibiotics for injection, which was developed by Hearst Company in Germany. Ability plays a role.

At present, the preparation of cefodizime sodium in the prior art all takes 7-ACA or the follow-up product cefotaxime acid of 7-ACA as raw material, easily produces by-products in the reaction process, affects product quality, and the purity is not high; 7-ACA is used as raw material to prepare cefodizime sodium with low yield, poor quality and long reaction time, which is not conducive to continuous and large-scale industrial production. Therefore, research and development of synthetic techniques with simple process, high yield, high quality, and suitable for large-scale industrial production have become a top priority.

Cefodizime sodium is mainly prepared from cefodizime acid, and the most important thing in the preparation process is the dissolution of cefodizime acid. U.S. Patent No. 5,126,445 discloses suspending cefodizime acid in water, adding triethylamine dropwise to dissolve it, and adding sodium isooctanoate solution dropwise to the clear solution to precipitate cefodizime sodium. The resulting product has a darker color and needs to be refined, which affects the product quality and yield. U.S. Patent No. 4,590,267 discloses dissolving cefodizime sodium with sodium bicarbonate, adding alcohol dropwise to separate out cefodizime sodium, and dissolving it with sodium bicarbonate. The dissolution time is long, and the resulting product easily contains undissolved sodium bicarbonate, which affects the product. quality. Chinese patent CN101239985 discloses suspending cefodizime acid in a two-phase system, adding sodium isooctanoate and stirring to completely dissolve, layering, adding alcohol to the water layer to precipitate cefodizime sodium, and the two-phase system is selected from dichloromethane/water , tetrachloromethane/water, toluene/water or ethyl acetate/water, a large amount of organic solvents are used in this method, and the recovery rate is low, pollutes the environment, the cost is higher, the operation steps are many and complicated, and the product purity is lower . Chinese patent CN101723958B discloses suspending cefodizime acid in ethanol, adding dropwise triethylamine to dissolve, decolorizing, adding dropwise ethanol solution crystallization of sodium isooctanoate to the clear solution, suction filtration, and washing with absolute ethanol and acetone , dry to obtain cefodizime sodium, a large amount of ethanol is used in this method, the production cost is higher, and the operation steps are many and complicated.

Contents of the invention

In the present invention, for convenience of description, GCLE, that is, 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester, is referred to as compound I for short; Methylmercaptothiazole acetic acid is referred to as compound II for short; ( 6R,7R)-7-amino]-3-[[(5-carboxymethyl-4-methyl-2-thiazolyl)thio]methyl]-8-oxo-5-thia-1- Azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid is referred to as compound Ⅲ; AE active ester is referred to as compound Ⅳ; cefodizime sodium is referred to as compound Ⅴ.

For the deficiencies in the prior art, the object of the present invention is to provide a kind of method that replaces traditional 7-ACA with GCLE as starting material to prepare cefodizime sodium, and synthesize cefodizime sodium in two steps with GCLE, which solves the existing problem There is the problem of high polymer content in the technology, the synthesis reaction steps are short, the side reactions are few, the operation is simple, the yield is high, and the obtained product has high purity.

A preparation method of cefodizime sodium, using compound I as a starting material, the specific steps comprising:

(1) Suspend compound I and compound II in an aqueous solution containing an organic solvent, heat to 50°C, stir until clarification, add a catalyst, and adjust with a sodium bicarbonate solution or sodium carbonate solution with a mass fraction of 8%-12%. pH 5.0-5.5, react for 1-2 hours, add halogenated acid for hydrolysis, add activated carbon for decolorization, wash, adjust pH to 2.5-3.5 with ammonia water with a mass fraction of 25%-28%, grow crystals, suction filter, wash, Vacuum drying to obtain light yellow or off-white crystalline powder, namely compound III;

(2) In the mixed solvent, add compound III and compound IV and stir, then dropwise add organic base to react for 1-2 hours, add activated carbon to decolorize, filter, wash, add dropwise salt-forming agent solution, stir slowly until turbidity comes out crystallization, crystal growth, suction filtration, washing, and vacuum drying to obtain white or off-white compound V, namely cefodizime sodium.

The synthetic route is:

Wherein, the catalyst described in step (1) is metal bromide or metal iodide, preferably sodium iodide, sodium iodide is relatively easy to participate in the halogenation reaction, the dosage is small and the reaction is thorough, and the effect is better; step (1) The halogenated acid described in is trifluoroacetic acid.

In the step (1), the mass ratio of compound I to compound II is 1:0.41-0.47. Since compound I is more costly than compound II, this ratio range can ensure that the high-cost compound I reacts completely; compound I and the catalyst The mass ratio is 1:0.01-0.03. If it is higher than this ratio range, the reaction will be incomplete and the residue will be high. If it is lower than this ratio range, the color of the product will be heavier, and it will cause waste of catalyst; compound I and halogenated acid The mass ratio is 1:1.8-4.7, and this ratio range can ensure the complete removal of the 4-position protecting group carboxyl group in compound I, otherwise the 4-position protecting group cannot be completely removed, increasing impurities in the product, or causing waste.

The organic solvent described in the step (1) is acetone, and the volume ratio of acetone and water in the aqueous solution containing the organic solvent is 20:1-2, and the reaction is relatively thorough within this ratio range, and the yield is high, and the product The color is better.

The mass ratio of compound III to compound IV described in step (2) is 1:1.37-1.71, higher than this ratio range, resulting in incomplete reaction of compound III and increased impurities; lower than this ratio, resulting in compound IV waste, and post-processing is also more troublesome.

The mixed solvent described in step (2) is a solvent composed of acetone or toluene and alcohol, and the alcohol is ethanol; the mixed solvent is preferably a solvent composed of acetone and ethanol, and the volume ratio of acetone and ethanol is 1- 3:1. The role of the mixed solvent is to reduce the solubility of cefodizime sodium, improve the yield, and have a good removal effect on impurities with low polarity, thereby improving the purity of the product. This ratio range is the optimum solvent amount, not only has low solubility to the generated sodium salt, but also has a high yield, and the crystal form of the product is a regular rod-shaped crystal form, which is easy to dry and pack.

The organic base described in step (2) is one of pyridine or triethylamine or diethylamine or tert-butylamine or aniline or morpholine, preferably triethylamine. The main function of the organic base is dissolution and catalysis, but from the yield and color of the product, the effect of triethylamine is milder in terms of alkalinity.

The salt-forming agent described in step (2) is one of sodium isooctanoate, sodium methoxide or sodium acetate, the mass ratio of compound III to the salt-forming agent is 1:0.15-0.95, and the amount of the salt-forming agent is too small , The salt formation is not complete, which affects the product yield. The dosage of the salt formation agent is too large, and the residual organic acid is high, leading to allergies. The salt-forming agent described therein is preferably sodium isooctanoate, and this is because the solubility of sodium isooctanoate in an organic solvent is relatively large, and the by-product organic acid generated is also relatively easy to remove.

The temperature range of the crystal growing process in the step (1) and the step (2) is 10°C-15°C, and the crystal growing time is 1 hour.

The salt-forming agent solution in the step (2) is a solution formed by dissolving the salt-forming agent in a mixed solvent. In the step (2), in the mixed solvent, add compound III and compound IV and stir, then dropwise add an organic base to react for 1-2 hours, add activated carbon for decolorization, filter, and wash; dissolve the salt-forming agent in the mixed solvent for dripping Add, slowly stir until turbid and crystallize, in order to precipitate more crystals, add acetone or toluene dropwise, grow the crystals, filter with suction, wash, and dry in vacuo to obtain white or off-white compound V, namely cefodizime sodium.

GCLE, namely 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester, is following 7-ACA, 7-ADCA (7-amino-3-desacetoxy cephalosporanic acid) Another synthetic cephalosporin drug nucleus, which can replace 7-ACA for the preparation of cephalosporins, its C-3 position is -CH ₂ Cl, which can be used as a lead compound to prepare a C-3 position containing a double bond A series of cephalosporins such as thiomethyl, nitrogen methyl, etc. The chlorine on the C-3 increases the reactivity, and the carboxyl group at the C-4 position and the amino group at the C-7 position have been protected, which can reduce the occurrence of side reactions when reacting at the C-3 position, and the obtained product has high purity and good appearance color. When GCLE is used as the mother nucleus to produce cephalosporins, the product yield is higher, the production process is simpler, the production conditions are milder, and the product cost is lower. GCLE is prepared from the cheap penicillin G potassium salt as the starting material, and the product cost is low, and the price is only about 60% of the price of 7-ACA. GCLE was first developed and produced by Japan's Otsuka Chemical Co., Ltd., and has a history of more than ten years. In recent years, the synthesis and production technology of GCLE in China has been very mature, coupled with the continuous expansion of domestic penicillin production capacity and great advantages in fermentation technology, The price of GCLE has dropped significantly. At present, it is not only supplied for domestic use, but also exported in large quantities. GCLE's synthetic cephalosporins have shown strong advantages in quality and cost.

The present invention compares with prior art, and its beneficial effect is:

1. Using GCLE instead of traditional 7-ACA as the starting material to synthesize cefodizime sodium, the product yield is higher, the production process is simpler, the production conditions are milder, and the product cost is lower. Because the cost of preparing 7-ACA by chemical method is too high, it is difficult to buy, and the protein content of 7-ACA prepared by enzymatic method is high, resulting in high polymer content of the final product, and the probability of allergies during medication is large. Cefodizime sodium according to the present invention The preparation method solves the problem of high polymer content in the final product, the high polymer content is reduced from 1.0% to less than 0.1%, and the purity is improved at the same time, the purity is above 99.8%;

2. In the mixed solvent, compound III and compound IV are reacted with an organic base to generate cefodizime acid, and activated carbon is added for decolorization. The decolorized reaction solution is not subjected to separation and purification steps, and the salt-forming agent is dissolved in the mixed solvent and dripped directly The salt addition solution reacts to generate cefodizime sodium, the use of the mixed solvent reduces the solubility of cefodizime sodium, improves the yield, and has a good removal effect for small polar impurities, which improves the product quality. Purity; and the intermediate cefodizime acid synthesized in the prior art needs to go through the process steps of crystallization, washing and drying, and also needs to add solvent again to dissolve in the reaction with the salt-forming agent. In the present invention, step (2) is completed in the mixed solvent, which saves the intermediate separation steps, shortens the process steps, and saves time; the raw material ratio and the use of the mixed solvent described in the present invention improve the yield, Make the product yield reach more than 90%.

The preparation method of cefodizime sodium provided by the invention has short steps and few side reactions, solves the problem of high polymer content in the final product, reduces the high polymer content from 1.0% to below 0.1%, and improves the purity, the product The purity is more than 99.8%. The ratio of the raw materials and the use of the mixed solvent have improved the yield, so that the product yield can reach more than 90%. The invention shortens the process steps, saves time, has simple process, high yield, low cost, high product purity, cheap and easy-to-obtain raw materials, and is suitable for industrialized production.

Description of drawings

Accompanying drawing 1 is the HPLC collection of illustrative plates of cefodizime sodium of embodiment 1 of the present invention;

Accompanying drawing 2 is the HPLC collection of illustrative plates of embodiment of the present invention 2 cefodizime sodium;

Accompanying drawing 3 is the HPLC collection of illustrative plates of embodiment of the present invention 3 cefodizime sodium;

Accompanying drawing 4 is the HPLC spectrum of cefodizime sodium of embodiment 4 of the present invention.

Detailed ways

The present invention will be further described below in conjunction with the embodiments, which are only several specific implementation forms of the present invention, and many variations and improvements can be made by those skilled in the art. All modifications or improvements that do not exceed the scope of the claims should be regarded as the scope of the present invention.

Example 1

The preparation method of cefodizime sodium adopts compound I as a starting material, and the specific steps include:

(1) Add 30g of compound I (GCLE) and 12.3g of compound II into a system containing 200mL of acetone and 20mL of water, heat to 50°C, stir until clear, add 0.3g of sodium iodide, and use a mass fraction of 10% sodium carbonate Adjust the pH of the solution to 5.0, react for 2 hours, add 100 g of trifluoroacetic acid for hydrolysis, add 1.5 g of activated carbon for decolorization, wash with a mixture of 10 mL of acetone and 1 mL of water, adjust the pH to 3.0 with 25% ammonia water, and culture at 10 °C. crystallize for 1 hour, filter with suction, wash with 100mL of water and 100mL of acetone respectively, and dry in vacuo to obtain 22.1g of compound III with a yield of 92% and a purity of 98.76%;

(2) Add 20g of compound III and 27.4g of compound IV into a mixed solvent system containing 100mL of toluene and 100mL of methanol, dropwise add 23mL of triethylamine, react at 5°C for 1.5hr, add 1g of activated carbon for decolorization, filter, 5mL of toluene and 5mL of methanol Wash the mixture and set aside;

Dissolve 19g of sodium isooctanoate in a mixed solution of 25mL of toluene and 25mL of methanol, slowly drop it into the above-mentioned standby reaction solution, stir slowly until turbid and crystallize, add dropwise 100mL of toluene, grow crystals at 10°C for 1 hour, and filter with suction. After washing with 50 mL of toluene and drying in vacuo, 28.5 g of compound V was obtained with a yield of 91%, a purity of 99.84%, and a high polymer content of 0.083%.

Example 2

The preparation method of cefodizime sodium adopts compound I as a starting material, and the specific steps include:

(1) Add 30g of compound I (GCLE) and 13.2g of compound II into a system containing 200mL of acetone and 15mL of water, heat to 50°C, stir until clear, add 0.7g of sodium bromide, and use a mass fraction of 8% bicarbonate Adjust the pH to 5.5 with sodium solution, react for 1 hour, add 141g of trifluoroacetic acid for hydrolysis, add 1.5g of activated carbon for decolorization, wash with a mixture of 10mL of acetone and 0.75mL of water, adjust the pH to 3.5 with 28% ammonia water, 12°C Cultivate the crystal for 1 hour, filter with suction, wash with 100 mL of water and 100 mL of acetone respectively, and dry in vacuo to obtain 21.8 g of compound III with a yield of 91% and a purity of 98.62%;

(2) Add 20g of compound III and 34.2g of compound IV into a mixed solvent system containing 200mL of toluene and 100mL of ethanol, add dropwise 23mL of diethylamine, react at 10°C for 1.5hr, add 1g of activated carbon for decolorization, filter, 10mL of toluene and 5mL of ethanol Wash the mixture and set aside;

Dissolve 3g of sodium methoxide in a mixed solution of 50mL of toluene and 25mL of ethanol, slowly drop it into the above-mentioned standby reaction solution, stir slowly until turbid and crystallize, add dropwise 100mL of toluene, grow crystals at 12°C for 1 hour, filter with suction, 50mL After washing with toluene and vacuum drying, 28.2 g of compound V was obtained, with a yield of 90%, a purity of 99.80%, and a high polymer content of 0.09%.

Example 3

The preparation method of cefodizime sodium adopts compound I as a starting material, and the specific steps include:

(1) Add 30g of compound I (GCLE) and 14.1g of compound II into a system containing 200mL of acetone and 10mL of water, heat to 50°C, stir until clear, add 0.9g of potassium bromide, and use 12% carbonic acid Adjust the pH to 5.2 with sodium hydrogen solution, react for 2 hours, add 54g of trifluoroacetic acid for hydrolysis, add 1.5g of activated carbon for decolorization, wash with 10mL of acetone and 1mL of water mixture, adjust the pH to 3.5 with 26% ammonia water, 15°C Cultivate the crystal for 1 hour, filter with suction, wash with 100 mL of water and 100 mL of acetone respectively, and dry in vacuo to obtain 21.5 g of compound III with a yield of 90% and a purity of 98.56%;

(2) Add 20g of compound III and 30g of compound IV into a mixed solvent system containing 100mL of acetone and 100mL of methanol, dropwise add 23mL of tert-butylamine, react at 6°C for 1.5hr, add 1g of activated carbon for decolorization and filtration, wash with a mixture of 5mL of acetone and 5mL of methanol, and set aside ;

Dissolve 10g of sodium acetate in a mixed solution of 25mL of acetone and 25mL of methanol, slowly drop it into the above-mentioned standby reaction solution, stir slowly until turbid and crystallize, add dropwise 100mL of acetone, grow the crystal at 15°C for 1 hour, suction filter, 50mL After washing with acetone and vacuum drying, 28.4 g of compound V was obtained, with a yield of 90.6%, a purity of 99.86%, and a high polymer content of 0.08%.

Example 4

The preparation method of cefodizime sodium adopts compound I as a starting material, and the specific steps include:

(1) Add 30g of compound I (GCLE) and 13g of compound II into a system containing 200mL of acetone and 20mL of water, heat to 50°C, stir until clear, add 0.7g of potassium iodide, and adjust with 9% sodium bicarbonate solution pH to 5.3, react for 2 hours, add 100g of trifluoroacetic acid for hydrolysis, add 1.5g of activated carbon for decolorization, wash with 10mL of acetone and 1mL of water mixture, adjust the pH to 2.5 with 27% ammonia water, grow crystals at 13°C for 1 hour , filtered with suction, washed with 100mL of water and 100mL of acetone respectively, and dried in vacuo to obtain 21.7g of compound III with a yield of 91.5% and a purity of 98.60%;

(2) Add 20g of compound III and 30g of compound IV into a mixed solvent system containing 100mL of acetone and 100mL of ethanol, add dropwise 23mL of pyridine, react at 8°C for 1.5 hours, add 1g of activated carbon for decolorization, filter, wash with 5mL of acetone and 5mL of ethanol, and set aside;

Dissolve 10 g of sodium isooctanoate in a mixed solution of 25 mL of acetone and 25 mL of ethanol, slowly drop it into the above-mentioned standby reaction solution, stir slowly until turbid and crystallize, add dropwise 100 mL of acetone, grow crystals at 13°C for 1 hour, and filter with suction. After washing with 50 mL of acetone and drying in vacuum, 28.2 g of compound V was obtained with a yield of 90%, a purity of 99.82%, and a high polymer content of 0.09%.

Can find out according to embodiment 1-4, the preparation method of cefodizime sodium provided by the present invention, step is short, and side reaction is few, has solved the problem that final product high polymer content is high, and high polymer content is below 0.1%, The product purity is more than 99.8%, and the product yield is more than 90%. The invention shortens the process steps, saves time, has simple process, high yield, low cost, high product purity, cheap and easy-to-obtain raw and auxiliary materials, and is suitable for industrial production.

Claims (1)

1. a preparation method for Cefodizime Sodium, is characterized in that: employing chemical compounds I is starting raw material, and concrete steps comprise:

(1) chemical compounds I and compound ii are suspended in the aqueous solution containing organic solvent, are heated to 50 ℃, stir to clarify, add catalyzer, the sodium hydrogen carbonate solution that is 8%-12% with massfraction or sodium carbonate solution are adjusted pH to 5.0-5.5, reaction 1-2 hour, add after halogenated acid hydrolysis, then add activated carbon decolorizing, washing, the ammoniacal liquor that is 25%-28% with massfraction is adjusted pH to 2.5-3.5, growing the grain, suction filtration, washing, vacuum-drying, obtains light yellow or off-white color crystalline powder, i.e. compound III;

(2) in mixed solvent, compound III and compounds Ⅳ are added to rear stirring, then drip organic bases reaction 1-2 hour, add activated carbon decolorizing, filter, washing, drip salt forming agent solution, slowly be stirred to muddiness and go out crystalline substance, growing the grain, suction filtration, washing, vacuum-drying, obtains white or off-white color compound V, i.e. Cefodizime Sodium;

Synthetic route is:

；

Catalyzer described in step (1) is metal bromide or metal iodide;

Halogenated acid described in step (1) is trifluoroacetic acid;

Chemical compounds I in described step (1): compound ii: catalyzer: the mass ratio of halogenated acid is 1:0.41-0.47:0.01-0.03:1.8-4.7;

Organic solvent described in step (1) is acetone, and the described volume ratio containing acetone in the aqueous solution of organic solvent and water is 20:1-2;

The mass ratio of the compound III described in step (2) and compounds Ⅳ is 1:1.37-1.71;

Mixed solvent described in step (2) is the solvent that acetone and ethanol form, and its volume ratio is 1-3:1;

Organic bases described in step (2) is a kind of of pyridine or triethylamine or diethylamine or TERTIARY BUTYL AMINE or aniline or morpholine;

Salt forming agent described in step (2) is Sodium isooctanoate or sodium methylate or sodium-acetate, and the mass ratio of compound III and salt forming agent is 1:0.15-0.95.