CN100361995C - One-step preparation process of injection-grade sterile cefotaxime sodium - Google Patents

Abstract

The invention relates to a preparation process of cefotaxime sodium. In a solvent, 7-ACA and AE-active ester are reacted under the action of amine intermediate reactants, benzothiazole co-solvent is added, and sodium is added to form a salt It is prepared by reacting and crystallizing with the agent. The reaction solvent is a mixed solvent composed of benzene organic solvent, ethyl acetate or acetone and alcohol organic solvent. Stir 7-ACA and AE-active ester, react until clear, and then Add benzothiazole co-solvent, sterilize and filter and directly add sodium salt-forming agent to carry out salt-forming reaction. When the reaction becomes turbid, carry out crystal growth treatment, and then use the insoluble organic solvent of cefotaxime sodium to separate the crystals, and finally undergo conventional After crystallization, the finished product of cefotaxime sodium can be obtained. Using a mixed solvent to prepare cefotaxime sodium directly from 7-ACA, one-step process operation, good crystallization, short production cycle, low labor intensity, low power consumption, low production cost, and can increase product yield, and the use of solvent The amount is reduced, which reduces the harm of the solvent to the operator, and is beneficial to the industrial application.

Description

One-step preparation process of injection-grade sterile cefotaxime sodium

technical field

The invention relates to a preparation process of cefotaxime sodium, which belongs to the technical field of compound preparation.

Background technique

Cefotaxime sodium is a third-generation cephalosporin derivative, widely used in the treatment of sepsis, suppurative meningitis and respiratory tract, urinary tract, biliary tract, bone and joint, skin and soft tissue, abdominal cavity and digestive tract caused by sensitive bacteria. , facial features, genitals and other parts of the infection. The existing cefotaxime sodium preparation process is divided into two steps. In a single solvent of dichloromethane, 7-ACA and AE-active ester react under the effect of amine intermediate reactant, then add hydrochloric acid to carry out acidification, and then Cool down and decrystallize to obtain cefotaxime; the second step is to dissolve cefotaxime, add a salt-forming agent to carry out a salt-forming reaction, and use acetone to precipitate crystals. Two-step process operation, poor crystallization, affects product quality, large solvent usage, serious pollution, high labor intensity, long production cycle, large power consumption, high production cost, and low product yield.

Contents of the invention

The object of the present invention is to provide a one-step preparation process of injection-grade sterile cefotaxime sodium, which has less solvent usage, low labor intensity, short production cycle, low production cost, high product yield and good quality.

The one-step preparation process of injection-grade sterile cefotaxime sodium of the present invention, in solvent, reacts by 7-ACA and AE-active ester under the effect of amine intermediate reactant, adds benzothiazole cosolvent , and then add sodium salt-forming agent to react and precipitate crystallization. The reaction solvent is a mixed solvent composed of benzene organic solvent, ethyl acetate or acetone and alcohol organic solvent. Stir 7-ACA and AE-active ester , react until clarified, then add benzothiazole co-solvent, sterilize and filter and directly add sodium salt-forming agent for salt-forming reaction, when the reaction becomes turbid, carry out crystal growth treatment, and then use the insoluble organic solvent of cefotaxime sodium to crystallize Precipitate, and finally obtain the finished product of cefotaxime sodium through conventional crystallization post-treatment.

The reaction equation is: (see next page)

Because the process of the present invention adopts the mixed solvent, it is not necessary to make cefotaxime at first, and then carry out the salt-forming reaction to prepare cefotaxime sodium, but directly prepare cefotaxime sodium from 7-ACA, one-step process operation, which simplifies the process process, the crystallization situation is good, the production cycle is short, the time is shortened by half, the labor intensity is small, the power consumption is small, the production cost is low, and the content can be increased by about 2%, and the yield is more than 88% (calculated by 7-ACA), and The amount of solvent used is reduced to only 75% of the original, which reduces the harm of solvent to operators.

In the present invention:

The composition volume ratio of mixed solvent is:

Benzene organic solvent, ethyl acetate or acetone:alcohol organic solvent=1:(1～0.5).

The benzothiazole co-solvent is one of bis(trichloromethyl)carbonate, trichloromethyl chloroformate, hydrogen halide or other halides.

Benzene organic solvents are toluene or xylene and the like.

Alcoholic organic solvents are methanol, ethanol or isopropanol and the like.

Amine intermediate reactant is triethylamine, diisopropylamine or tertiary amine etc.

The salt-forming agent is one of organic or inorganic sodium salts such as sodium isooctanoate, sodium acetate (sodium acetate), sodium methylate, and sodium carbonate, and can be directly used as a solid or as a solution. The solution is prepared by dissolving or mixing sodium salt in a mixed solvent, and the same solvent is used for easy handling.

The insoluble organic solvents of cefotaxime sodium are toluene, acetone, ethyl acetate, absolute ethanol or isopropanol, etc., which can be selected or used in combination.

Salt formation reaction When the reaction solution becomes turbid, adding cefotaxime sodium powder as a seed crystal and then carrying out crystal growth treatment will improve the crystallization situation and crystallization quality.

The washing solution can be a mixture of ethyl acetate and absolute ethanol or dichloromethane and methanol, and the mixing volume ratio can be 10: (1-2).

Using sodium salt as a salt-forming agent, after the crystallization filter cake is washed, it is better to use an acetone solution with a volume ratio of 3 to 5% of water for stirring and washing treatment to ensure product quality.

The production of the product must comply with the requirements of the industry, and other process conditions not mentioned in detail are the same as the conventional operation, such as the ingredients of the reactants meet the requirements of the reaction equation, the ratio of the amount of amine intermediate reactants to 7-ACA, the benzothiazole auxiliary The addition of solvent and salt-forming agent (the amount of co-solvent and salt-forming agent added is 0.5-2% of the 7-ACA feeding amount), the reaction temperature is 4-10°C, the crystal growth time is 0.5-1 hour, the crystallization washing requirements, The drying temperature is 40-50°C, the vacuum degree of vacuum drying is controlled at 0.095-0.099MPa, and so on.

The process of the present invention adopts a mixed solvent to directly prepare cefotaxime sodium from 7-ACA. One-step process operation simplifies the process, good crystallization, short production cycle, low labor intensity, low power consumption, low production cost, and The product yield is improved, and the amount of solvent used is reduced, which reduces the harm of the solvent to operators, and is beneficial to industrial application.

Detailed ways

The present invention will be further described below in conjunction with embodiment.

Example 1

The preparation technology of cefotaxime sodium of the present invention is as follows:

Add 120ml of toluene and methanol with a volume ratio of 1:1 to form a mixed solvent, 20ml of triethylamine, cool down to 5°C, add 20g of 7-ACA, 28g of AE-active ester, and keep at 5°C for 60 Minutes, after the reaction is clarified, add 3 milliliters of concentrated hydrochloric acid, add sodium isooctanoate solution salt forming agent and 0.1 g sodium bisulfite antioxidant at room temperature, react for 10 minutes, then seed and grow crystals for 30 minutes, and then add toluene dropwise 150ml, the temperature of the dropwise addition of toluene is controlled at 20°C, and the drop is completed in 2 hours. After the drop is completed, the crystal is grown for 30 minutes and the material is discharged. The mixture of 50ml ethyl acetate and 5ml absolute ethanol is used to wash the cake, and then add the cake Stir and wash in the mixture of 140ml acetone and 6ml water for 30 minutes, then discharge the material cake, wash the material cake with a small amount of acetone, and dry the wet product material for 3 hours at 50°C and a vacuum of -0.097MPa. Receive dry product cefotaxime sodium 31 grams, product yield is 88% (calculated as 7-ACA).

Wherein: the salt-forming agent is made by dissolving 13 grams of sodium isooctanoate into a mixed solution of 15 ml of toluene and 15 ml of methanol.

Example 2

Add 120ml of toluene and methanol with a volume ratio of 1:1 to form a mixed solvent, 20ml of triethylamine, cool down to 7°C, add 20g of 7-ACA, 28g of AE-active ester, and keep it at 7°C for 63 Minutes, add 3ml of concentrated hydrochloric acid after the reaction is clarified, add a salt-forming agent (13 grams of sodium isooctanoate dissolved in a mixture of 15ml of toluene and 15ml of methanol) at room temperature, 0.1g of sodium bisulfite, then add dropwise toluene to slightly When the crystal is cloudy, grow the crystal for 30 minutes, and then add the remaining toluene dropwise. The temperature of the dropwise addition of toluene is controlled at 22°C, a total of 120ml is added, and the drop is completed within 1.5 hours. Wash the cake with a mixture of ester and 5ml of isopropanol, then add the cake to a mixture of 140ml of acetone and 6ml of water, stir and wash for 20 minutes, then discharge the cake, then wash the cake with a small amount of acetone, wet material Vacuum drying at 50°C for 3 hours can yield 31.2 g of dry product cefotaxime sodium. The yield is 88.1%.

Example 3

Add 120ml of toluene and methanol at a volume ratio of 1:0.8 to the three-neck flask to form a mixed solvent, 20ml of triethylamine, cool down to 4°C, add 20g of 7-ACA, 28g of AE-active ester, and keep at 5°C for 65 Minutes, add 1g of trichloromethyl chloroformate after the reaction is clarified, add a salt-forming agent (13 grams of sodium isooctanoate dissolved in 30ml of mixed solvent) at room temperature, 0.1g of sodium bisulfite, add crystal seeds to grow crystals for 30 minutes Minutes, then add the remaining toluene dropwise, the temperature of the dropwise addition of toluene is controlled at 18°C, a total of 120ml is added, and the drop is completed within 1.8 hours. Wash the cake with a mixture of ethanol, then add the cake to a mixture of 150ml acetone and 6ml water, stir and wash for 25 minutes, then discharge the cake, wash the cake with a small amount of acetone, and dry the wet product in vacuum at 50 degrees .

Example 4

Add 120ml of toluene and methanol at a volume ratio of 1:0.5 to the three-necked flask to form a mixed solvent, 20ml of triethylamine, cool down to 6°C, add 20g of 7-ACA, 28g of AE-active ester, and keep at 5°C for 55 Minutes, add 1g of trichloromethyl chloroformate after the reaction is clarified, add a salt-forming agent (13 grams of sodium isooctanoate dissolved in 30ml of mixed solvent) at room temperature, 0.1g of sodium bisulfite, then add dropwise toluene to slightly When the crystal is cloudy, grow the crystal for 30 minutes, and then add the remaining toluene dropwise. The temperature of the dropwise addition of toluene is controlled at 19°C, and a total of 120ml is added, and the drop is completed within 1.6 hours. Wash the cake with a mixture of 5ml of isopropanol, then add the cake to a mixture of 150ml of acetone and 6ml of water, stir and wash for 25 minutes, then discharge the cake, wash the cake with a small amount of acetone, and vacuum the wet product at 50 degrees Allow to dry for 3 hours.

Example 5

Add 120ml of toluene and methanol at a volume ratio of 1:0.6 to the three-necked flask to form a mixed solvent, 20ml of triethylamine, cool down to 6.5°C, add 20g of 7-ACA, 28g of AE-active ester, and keep at 6.5°C for 60 Minutes, add 1g of bis(trichloromethyl)carbonate after the reaction is clarified, add 10 grams of sodium isooctanoate and 0.1 g of sodium bisulfite as a salt-forming agent at room temperature, then add toluene dropwise to grow crystals for 30 minutes when slightly turbid, and then Then add the remaining toluene dropwise. The temperature of the dropwise addition of toluene is controlled at 23°C. A total of 120ml is added, and the drop is completed within 1.8 hours. Material cake, then add material cake to the mixed solution of 140ml acetone and 6ml water and stir and wash for 30 minutes, then discharge the material cake, and then wash the material cake with a small amount of acetone, and vacuum dry the wet product material at 50 degrees for 3 hours.

Embodiment 6-10

The toluene in the mixed solvent is replaced by xylene, and other situations are respectively the same as in Examples 1-5.

Examples 11-15

The toluene in the mixed solvent was replaced with ethyl acetate, and other conditions were respectively the same as in Examples 1-5.

Examples 16-20

The toluene in the mixed solvent is replaced by acetone, and the other conditions are the same as in Examples 1-5 respectively.

Examples 21-40

The methanol in the mixed solvent was replaced with ethanol, and other conditions were the same as in Examples 1-20.

Examples 41-80

The amine intermediate reactant triethylamine was replaced with diisopropylamine, and the other conditions were the same as in Examples 1-40.

Insoluble organic solvents are selected as two or more of them in any proportion to be mixed for the test, and the test results prove that it is acceptable.

Claims (7)

1. A one-step preparation process of injection-grade sterile cefotaxime sodium, in solvent, reacts under the effect of triethylamine or diisopropylamine amine class intermediate reactant by 7-ACA and AE-active ester, It is prepared by adding trichloromethyl chloroformate or benzothiazole hydrogen chloride as a co-solvent, and then adding a sodium salt-forming agent for reaction and precipitation of crystallization. It is characterized in that the reaction solvent is made of benzene organic solvent, ethyl acetate or acetone and alcohols Mixed solvent composed of organic solvent, stir 7-ACA and AE-active ester, react until clear, then add benzothiazole co-solvent, sterilize and filter, directly add sodium salt-forming agent for salt-forming reaction, when the reaction becomes turbid, Carry out the crystal growth treatment, then use the insoluble organic solvent of cefotaxime sodium to separate out the crystals, and finally go through conventional crystallization post-processing to obtain the finished product of cefotaxime sodium. 2. the one-step preparation technique of injection-grade sterile cefotaxime sodium according to claim 1 is characterized in that the composition volume ratio of mixed solvent is: benzene organic solvent, ethyl acetate or acetone: alcohol organic solvent = 1: (1～0.5). 3. according to claim 1 and the one-step preparation process of injection grade sterile cefotaxime sodium, it is characterized in that benzene organic solvent is toluene or dimethylbenzene. 4. according to claim 1 and the one-step preparation technique of injection grade sterile cefotaxime sodium, it is characterized in that the alcoholic organic solvent is a kind of in methyl alcohol or ethanol. 5. the one-step preparation process of injection-grade sterile cefotaxime sodium according to claim 1 is characterized in that the salt-forming agent is a sodium isooctanoate solution, which is dissolved in a mixed solvent and made by sodium isooctanoate. 6. the one-step preparation technique of injection-grade sterile cefotaxime sodium according to claim 1 is characterized in that the insoluble organic solvent of cefotaxime sodium is toluene, xylene, acetone, ethyl acetate, dehydrated alcohol or One or a mixture of isopropanol. 7. the one-step preparation process of injection-grade sterile cefotaxime sodium according to claim 6 is characterized in that after the crystallization filter cake is washed, then the acetone solution with a volume ratio of 3 to 5% water is used for stirring and washing deal with.