CN116640155A - A kind of preparation method of cillin medicine - Google Patents

Abstract

The invention relates to a preparation method of a penicillin drug, which comprises the following steps: mixing the cilind acid, the organic solvent, the organic alkali and the salifying agent, preparing the solution at the process temperature of 20-45 ℃ and separating out crystals to obtain the crystal; the organic base is primary amine or tertiary amine. The penicillin medicine prepared by the invention has good properties and stability, the impurity degradation risk in the preparation process is low, the content of related substances is low, and the yield reaches 90%; meanwhile, the method has simple process steps, is convenient for solvent recovery, and saves cost and process operation time.

Description

A kind of preparation method of cillin medicine

technical field

The invention belongs to the technical field of medicines, and in particular relates to a preparation method of penicillins.

Background technique

Penicillin drugs belong to the penicillin class of antibiotics and mainly include the following three categories: ① Aminopenicillins: ampicillin, amoxicillin, bahamicillin, pampicillin, etc., which are mainly used for Gram-positive bacteria sensitive to penicillin and some Gram-positive bacteria. Coli-negative bacilli such as Escherichia coli, Proteus, Bacillus aerogenes, Salmonella, Shigella and Influenza Bacillus, etc.; Oxicillin, nafcillin, etc., have good effects on β-lactamase-producing Staphylococcus; ③ Anti-Pseudomonas penicillins: carbenicillin, mezlocillin, piperacillin, ticarcillin, etc., have good effects on Gram The role of negative bacteria is stronger, antibacterial spectrum including Neisseria gonorrhoeae, Escherichia coli, Pseudomonas aeruginosa, Citrobacter, Enterobacter and Haemophilus and so on.

At present, there are three methods for industrial production of cillin drugs: spray drying, freeze drying and solvent crystallization. Among them, the spray drying method and the freeze drying method are not commonly used in the current industrial production due to high energy consumption and expensive equipment, resulting in high production costs. The solvent crystallization method is to dissolve cillinic acid in an organic solvent with an organic base, add an organic salt-forming agent containing sodium ions, and generate cillin sodium crystals. The solvent crystallization method does not require expensive special equipment, and the quality of the finished product is easy to control. Therefore, in the current Commonly used in industrial production.

Although the quality of cillin drugs prepared by the solvent crystallization method is usually better than the other two methods, there are still many things to be improved, such as:

A preparation method of ampicillin sodium is disclosed in the prior art. In the method, ampicillin acid trihydrate is reacted with diisopropylamine in absolute ethanol, and a methyl acetate solution of sodium isooctanoate is added for crystallization. The method introduces methyl acetate and ethanol with a small difference in boiling point, which is difficult to recycle, increases manufacturing costs and environmental protection pressure; at the same time, due to the influence of ethanol, the crystals obtained are mostly amorphous, resulting in poor properties of finished materials, related substances and Poor stability, difficult to separate and wash.

Disclosed a kind of preparation method of ampicillin sodium in the prior art, this method dissolves sodium isooctanoate in methanol, then adds sodium isooctanoate solution in the dichloromethane solution of ampicillin diisopropylamine salt, adds antisolvent Dichloromethane and seed crystal growth. This method introduces methanol and seed crystals. Due to the poor stability of the ampicillin ammonium salt solution, the introduction of methanol leads to a greater risk of degrading impurities, and the introduction of seed crystals increases the complexity of the process.

The prior art also discloses a preparation method of cloxacillin sodium, which dissolves sodium isooctanoate in methanol, then adds the sodium isooctanoate solution to a 1% aqueous solution of cloxacillin acid in butyl acetate, and then Add 11 times of butyl acetate to crystallize. This method also introduces methanol, which has a high risk of degradation and a large anti-solvent multiple, which affects the batch size.

Studies have also reported a preparation method of ampicillin sodium, which dissolves sodium isooctanoate in an organic solvent, then dissolves ampicillin trihydrate in an organic solvent containing diisopropylamine, and stirs in a crystallization tank Crystallization, after a large amount of crystals are precipitated, add an organic solvent, grow the crystals for 30 minutes, discharge, filter, wash, and dry the crystals obtained after washing under reduced pressure to obtain ampicillin sodium salt. But ampicillin sodium crystallizes out at high temperature in this method, and crystallization temperature has reached 50～60 ℃, when high temperature crystallization, especially temperature has surpassed 50 ℃, the index of dimer in its product is higher.

Therefore, based on the many defects in the current solvent crystallization method, it is necessary to study and improve the process of preparing penicillins.

Contents of the invention

The object of the present invention is to provide a preparation method of cillin drugs, which has simple steps, is convenient for solvent recovery, saves cost and process operation time, and the prepared cillin drugs have stable quality, low risk of impurity degradation and low content of related substances.

According to the present invention, the preparation method of a kind of cillin drugs provided by the present invention comprises the following contents: mixing cillin acid, an organic solvent, an organic base, and a salt-forming agent, controlling the temperature during the preparation process at 20-45°C, and depositing crystals to obtain ; The organic base is primary amine, tertiary amine.

Wherein said cillinic acid, organic solvent, organic base, the mixed mode of salt-forming agent include any one of the following:

After mixing the cillinic acid, the organic solvent and the organic base, the solid of the salt-forming agent or its solution is added to the mixed system;

Or after cillinic acid, organic solvent and organic base are mixed, the mixed system is added to the salt-forming agent or the salt-forming agent solution;

Or the salt-forming agent or the salt-forming agent solution can be mixed and dissolved with at least one of cillinic acid, organic solvent and organic base before mixing with the remaining components. For example, after the salt-forming agent can be mixed and dissolved with the organic solvent first, Then mix with cillinic acid and an organic base, or, after the salt-forming agent is firstly mixed with a mixed solution of cillinic acid and an organic solvent, and then mixed with the remaining organic base, etc.

According to the present invention, cillinic acid, organic solvent and organic base can be mixed in any way; after cillinic acid, organic solvent and organic base are mixed, the solid form or solution form of salt-forming agent can be added thereto after filtration or sterile filtration; The salt former solution may be unfiltered or sterile filtered.

In the method of the present invention, an organic base is added to the cillinic acid organic solvent mixed system, and the described cillinic acid, organic solvent, and organic base mixed system can be kept clear and not separated out after being dissolved, and then directly filtered into a crystallization tank to form a sodium salt, which simplifies The process steps are convenient for solvent recovery, saving cost and process operation time.

Further, the molar ratio of cillinic acid:organic base is 1:0.5-15; the molar ratio of cillinic acid:salt-forming agent is 1:1-15. According to some embodiments of the present invention, the molar ratio of cillinic acid:organic base is 1:0.5-10; the molar ratio of cillinic acid:salt-forming agent is 1:1-10. For example, the molar ratio of cillinic acid:organic base is 1:0.5-10. For example, the molar ratio of said cillinic acid: organic base can be 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, etc.

Further, the cillinic acid is selected from ampicillin acid, amoxicillin acid, cloxacillin acid, dicloxacillin acid, oxacillin acid, flucloxacillin acid, methicillin acid, nafcillin acid, carbenzyl Any one of the anhydrous substance of cillinic acid, mezlocillinic acid, piperacillinic acid, ticarcillinic acid and their hydrates.

Further, the organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, isopropanol, n-butanol, methanol, ethanol, ethyl acetate, isopropyl acetate, butyl acetate, formic acid At least one of aqueous or non-aqueous solvents of ethyl ester and methyl acetate.

In some embodiments, the organic solvent is selected from at least one of ethanol, n-butanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane or non-aqueous solvents .

In some embodiments, the water content of the organic solvent is 0.1%-5.0%.

The inventors have found that the increase of related substances including dimers in the system is mainly in the ammonium salt solution stage, that is, the degradation mainly occurs in the clarified ammonium salt solution stage, and the system gradually stabilizes as the salt replacement gradually proceeds. Therefore, the cillin sodium finished product prepared by the inventive method makes the stability of the ammonium salt solution significantly improve due to the use of relatively low pKa primary or tertiary amines as an organic base, and compared with the reported related patents, the product degrades in the production process The risk is low, the content of polymer impurities and other related substances in the product is significantly reduced, and the product quality is improved.

The present invention selects primary amine or tertiary amine as cillinic acid salt-forming agent and/or cosolvent, and its dissolving effect is better, compares with the related patent of having reported, can reduce solvent consumption, dwindle reaction system, improve production batch, increase product yield. efficiency, and ultimately improve production efficiency, greatly reduce production costs and improve economic benefits.

Wherein said primary amine can be selected from tert-butylamine, tert-octylamine, n-propylamine, cyclopropylamine, isopropylamine, n-butylamine, isobutylamine, cyclopropylmethylamine, n-pentylamine, isopentylamine, cyclohexaneamine , at least one of cycloheptaneamine and tromethamine;

The tertiary amine is at least one selected from triethylamine, N,N-diisopropylethylamine and DBU.

Further, the salt-forming agent is sodium isooctanoate and/or sodium acetate.

In some embodiments, the salt-forming agent can be a solid or a solution thereof; the salt-forming agent solution is obtained by dissolving the salt-forming agent in an organic solvent, and the organic solvent is selected from dichloromethane, chloroform , 1,2-dichloroethane, isopropanol, n-butanol, methanol, ethanol, ethyl acetate, isopropyl acetate, butyl acetate, ethyl formate, methyl acetate at least one.

The method of the present invention selects suitable primary amine or tertiary amine as organic base, carries out salt replacement reaction to obtain cillin sodium finished product in the ammonium cillinate solution obtained, and controls crystallization temperature and sodium isooctanoate solution or cillin acid solution simultaneously in the process of salt crystallization The feeding method and feeding time can effectively control the crystallization speed and crystallization process of the finished product, and can obtain the ideal target crystal form and crystal shape, avoid mixed crystals, improve the powder fluidity of the finished product, improve product quality and yield, and improve product quality. In the production feasibility of subsequent separation, washing and pre-drying, the working hours are significantly shortened, and the good crystallization performance of the material significantly improves the stability of the finished product.

The temperature is controlled at 32-40° C. during the preparation process of the cillin drugs described in the present invention.

Furthermore, in the present invention, after the crystals are precipitated, the crystals are grown for 5 to 120 minutes. After the crystal growth is completed, the materials are discharged and separated, washed, filtered, and dried to obtain the finished cillin-like medicines.

In the present invention, after the crystal growth is completed, conventional steps such as separation, washing, filtration, and drying can be performed after the feed liquid is cooled; further, the cooling temperature can be 0°C to 35°C, such as 0°C, 5°C, 10°C ℃, 15℃, 20℃, 25℃, 30℃, 32℃, 35℃ and so on.

In the present invention, after the crystal growth is completed, the feed liquid may not be cooled, but directly undergo conventional steps such as separation, washing, filtering, and drying.

As used herein, the terms "comprises," "including," "has," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, step, method or article comprising listed elements is not necessarily limited to those elements, but may include other elements not explicitly listed or inherent to such composition, step, method or article.

The method of the present invention selects suitable organic base, especially selects suitable primary amine or tertiary amine, controls the crystallization temperature, can effectively control the crystal form and crystal shape of cillin sodium, improves the product yield, and the yield can reach 90%, while increasing The fluidity of the powder is improved, thereby reducing the difficulty of separation, washing and drying of the product in the three-in-one process, and at the same time improving the stability of the finished product; the method of the invention has simple steps, is convenient for solvent recovery, and saves cost and process operation time.

Description of drawings

Fig. 1 is embodiment 1 sample chromatograms.

Detailed ways

In order to make the object, technical solution and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field of the invention. The terms used in the description of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention.

It should be clear that the experimental methods used in the following examples are conventional methods unless otherwise specified, and the materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1

Add 1109L of ethyl acetate to the dissolving tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to ampicillin, add sodium isooctanoate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; Amine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

Example 2

Add 1109L of ethyl acetate to the dissolution tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to cloxacillin, add sodium isooctanoate to the dissolution tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of cloxacillin; Tertiary octylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of cloxacillin sodium.

Example 3

Add 1109L of ethyl acetate to the dissolution tank, calculate the amount of sodium isooctanoate according to the molar ratio of oxacillin to 1:2, add sodium isooctanoate to the dissolution tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start the stirring, control the temperature at 32-40°C, add 400kg of oxacillin; Tertiary octylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, the feed is separated, washed, filtered and dried to obtain the finished product of oxacillin sodium.

Example 4

Add 1109L of ethyl acetate to the dissolving tank, calculate the amount of sodium isooctanoate according to the molar ratio of amoxicillin at 1:2, add sodium isooctanoate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of amoxicillin; calculate the amount of tert-octylamine added according to the molar ratio of amoxicillin to 1:3, and add in at a temperature of 32-40°C Tertiary octylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of amoxicillin sodium.

Example 5

Add 1109L of ethyl acetate to the dissolution tank, calculate the amount of sodium isooctanoate according to the piperacillin molar ratio of 1:2, add sodium isooctanoate to the dissolution tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of piperacillin; Tertiary octylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished piperacillin sodium product.

Example 6

Add 1109L of ethyl acetate to the dissolution tank, calculate the amount of sodium isooctanoate according to the molar ratio of ticarcillin to 1:2, add sodium isooctanoate to the dissolution tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ticarcillin; calculate the amount of tert-octylamine added according to the molar ratio of ticarcillin to 1:3, control the temperature at 32-40°C and add Tertiary octylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, the feed is separated, washed, filtered and dried to obtain the finished product of ticarcillin sodium.

Example 7

Add 1109L of ethyl acetate to the dissolving tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to ampicillin, add sodium isooctanoate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; calculate the amount of triethylamine added according to the molar ratio of ampicillin to 1:3, add triethylamine at the temperature of 32-40°C Amine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

Example 8

Add 1109L of ethyl acetate to the dissolving tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to ampicillin, add sodium isooctanoate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; Hexylamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

Example 9

Add 1109L of ethyl acetate to the dissolving tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to ampicillin, add sodium isooctanoate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; Heptaneamine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium isooctanoate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

Example 10

Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; Amine; react until the solution is clear and filter for later use. Add 1109L ethyl acetate to the dissolution tank, calculate the amount of sodium isooctanoate according to the molar ratio of 1:2 to ampicillin, add sodium isooctanoate to the dissolution tank, stir and dissolve until clarified, and then filter to the crystallization tank. Turn on the crystallization tank to stir, control the temperature to 40°C, add the above ampicillin tert-octylamine solution within 30 to 60 minutes, after the addition is complete, a large amount of crystals precipitate out, and grow the crystals for 5 to 120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

Example 11

Add 1385L of ethanol to the dissolving tank, calculate the amount of sodium acetate added according to the molar ratio of ampicillin to 1:2, add sodium acetate to the dissolving tank, stir and dissolve until clarified and set aside. Add 2918L of isopropanol to the reaction tank, start stirring, control the temperature at 32-40°C, add 400kg of ampicillin; Amine; react until the solution is clear and then filter to the crystallization tank. Turn on the crystallization tank and stir, control the temperature to 40°C, add the above-mentioned sodium acetate solution within 30-60 minutes, after the addition is complete, a large amount of crystals will precipitate out, and grow the crystals for 5-120 minutes. After the crystal growth is completed, the feed liquid is cooled to 32-35°C, discharged and separated, washed, filtered and dried to obtain the finished product of ampicillin sodium.

The preparation methods in Examples 8-11 of the present invention are also applicable to the preparation of cloxacillin sodium, oxacillin sodium, amoxicillin sodium, piperacillin sodium, ticarcillin sodium and other penicillin drugs.

Comparative Example 1: 100g of ampicillin trihydrate was added to 400ml of isopropanol, heated to reflux for 30min, and suction filtered to obtain ampicillin anhydrous acid, 46g of sodium isooctanoate was dissolved in 50ml of isopropanol and 130ml of ethyl acetate mixed In the solvent, obtain a sodium isooctanoate solution; add the obtained ampicillin anhydrous acid to a mixed solvent of 500ml isopropanol and 320m1 ethyl acetate, add 120ml diisopropylamine at 35°C to dissolve the ampicillin acid, and the dissolution is complete After controlling the temperature to 40°C, add the above-mentioned sodium isooctanoate solution dropwise for about 80 minutes, grow the crystal for 30 minutes, filter, wash twice with 300ml×2 ethyl acetate, and dry in vacuo to obtain ampicillin sodium.

Comparative Example 2: Dissolve 45g of sodium isooctanoate in a mixed solvent of 90ml methanol and 50ml of dichloromethane to obtain a sodium isooctanoate solution; add 100g of ampicillin trihydrate to 250ml of dichloromethane with a temperature control of 15°C, drop Add 45ml of diisopropylamine to dissolve the ampicillin acid. After the dissolution is completed, control the temperature at 20-25°C, quickly add the above-mentioned iso-sodium solution and 450ml of dichloromethane, then add 0.1g of ampicillin sodium seed crystals, let the crystal grow for 30 minutes and then start Stir, slowly add 450ml of dichloromethane dropwise, and drop it for about 4 hours, grow crystals for 30min, filter, wash twice with 100ml×2 dichloromethane, and dry in vacuo to obtain ampicillin sodium.

Comparative example 3: Dissolve 65g of sodium isooctanoate in 475ml of isopropanol to obtain a solution of sodium isooctanoate, and control the temperature at 55-65°C for later use; add 100g of ampicillin trihydrate to 375ml of isopropyl alcohol at a temperature of 15-25°C Alcohol and 42.5ml of diisopropylamine, after the dissolution is complete, add it to the above-mentioned sodium isooctanoate solution, control the temperature at 50-60°C, after most of the solids are precipitated, grow crystals for 30min, filter, wash with 100ml×3 isopropanol three times, Vacuum drying to obtain ampicillin sodium.

Comparative example 4: Dissolve 310g of sodium isooctanoate in 800ml of methylene chloride to obtain sodium isooctanoate solution for subsequent use; dissolve 100g of ampicillin trihydrate in 1500ml of methylene chloride, add 45g of anhydrous magnesium sulfate, and control the temperature for 3 -12°C, dehydrate until the water content is less than 1%, add diisopropylamine, stir for 30-60min, filter, and wash the filter cake with 150ml of dichloromethane and 7.5ml of diisopropylamine. Add 80% of the aforementioned sodium isooctanoate solution to the ammonium salt solution, grow the crystal for 40 minutes, add the remaining iso-sodium solution, grow the crystal for 40 minutes, filter, wash twice with 120ml×2 dichloromethane, and dry in vacuo to obtain ampicillin sodium.

Comparative Example 5: Dissolve 37g of sodium isooctanoate in 113g of methyl acetate to obtain sodium isooctanoate solution, and keep the temperature at 4°C for later use; dissolve 60g of ampicillin trihydrate in 91g of absolute ethanol and 43g of diisopropylamine, dissolve After completion, the temperature is controlled at 2°C, and activated carbon is adsorbed. After the adsorption is completed, the temperature is controlled at 0°C, the aforementioned sodium isooctanoate solution is added, the crystals are grown for 80 minutes, filtered, washed twice with 20ml×2 methyl acetate, and vacuum-dried to obtain ampicillin sodium.

The test results of related substances, bulk density, yield, hygroscopicity and stability of ampicillin sodium prepared in Example 1 of the present invention are compared with the products in the comparative examples, see Table 1 and Table 2 below:

Table 1 Related substances and bulk density comparison

Note: NA means that the sample cannot be weighed due to deliquescence into liquid, not detected.

As can be seen from the above table, the dimer, single unknown impurity and other total impurities in Example 1 of the present invention are significantly smaller than those of the comparative examples, while the yield is relatively high, the bulk density is large, and the powder is relatively thick, which is beneficial to the production of three Filtration, washing and scraping in one; In terms of moisture absorption, Example 1 of the present invention has a lower moisture absorption effect than the comparative example.

Table 2 Stability Comparison

Remarks: 1) Investigation condition: 60±1°C; 2) The test sample is the sample of Example 1 of the present invention, and the reference substance is the sample prepared according to the method of Comparative Example 1.

As can be seen from the above table, after 30 days, the increment of the dimer impurity in the sample of Example 1 of the present invention in the stability investigation was 0.01, and the increment of the dimer impurity of the control sample was 0.65; the sample of Example 1 of the present invention had a single unknown impurity The increment of the single unknown impurity of the control sample is 0.01, and the increment of the single unknown impurity of the control sample is 0.29; the increment of the total mass of the sample of Example 1 of the present invention is 0.18, and the increment of the total miscellaneous of the control sample is 0.78; in sum, the inventive method makes the sample The stability was significantly better than that of the control sample.

The foregoing examples are illustrative only, and are used to explain some features of the methods described in the present invention. The appended claims are intended to claim the broadest scope conceivable and the embodiments presented herein are merely illustrations of selected implementations according to all possible combinations of embodiments. Accordingly, it is the applicant's intention that the appended claims not be limited by the selection of examples which characterize the invention. Certain numerical ranges used in the claims also include sub-ranges therein, and changes within these ranges should also be construed as being covered by the appended claims where possible.

Claims (10)

1. A preparation method of cillin drugs, characterized in that, comprising the following contents: mixing cillin acid, organic solvent, organic base, and salt-forming agent, and controlling the temperature of the preparation process at 20-45° C., and separating out crystals to obtain final product; Described organic base is primary amine, tertiary amine. 2. The preparation method according to claim 1, characterized in that, the molar ratio of cillinic acid: organic base is 1:0.5～10; the mol ratio of cillinic acid: salt-forming agent is 1:1～10. 3. preparation method according to claim 1, is characterized in that, described cillinic acid is selected from ampicillin acid, amoxicillin acid, cloxacillin acid, dicloxacillin acid, oxacillin acid, flucloxacillin acid , Methicillin acid, nafcillin acid, carbenicillin acid, mezlocillin acid, piperacillin acid, ticarcillin acid anhydrate and any one of their hydrates. 4. preparation method according to claim 1 is characterized in that, described organic solvent is selected from dichloromethane, chloroform, 1,2-ethylene dichloride, Virahol, n-butanol, methyl alcohol, ethanol, acetic acid At least one of aqueous or nonaqueous solvents of ethyl ester, isopropyl acetate, butyl acetate, ethyl formate, and methyl acetate. 5. preparation method according to claim 4, is characterized in that, described organic solvent is selected from the aqueous solution of ethanol, n-butanol, Virahol, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane or at least one of non-aqueous solvents. 6. The preparation method according to claim 5, characterized in that the water content of the water-containing organic solvent is 0.1%-5.0%. 7. preparation method according to claim 1, is characterized in that, described primary amine is selected from tert-butylamine, tert-octylamine, n-propylamine, cyclopropylamine, isopropylamine, n-butylamine, isobutylamine, cyclopropylmethylamine , at least one of n-pentylamine, isopentylamine, cyclohexaneamine, cycloheptaneamine, and tromethamine; The tertiary amine is at least one selected from triethylamine, N,N-diisopropylethylamine and DBU. 8. The preparation method according to claim 1, characterized in that, the salt-forming agent is sodium isooctanoate and/or sodium acetate. 9. The preparation method according to any one of claims 1-8, characterized in that, the temperature is controlled at 32-40° C. during the preparation process of the cillin drugs. 10. The preparation method according to any one of claims 1 to 8, characterized in that, after the crystals are separated out, the crystals are grown for 5 to 120 minutes, and after the crystal growth is finished, the materials are discharged and separated, washed, filtered, and dried to obtain the finished product of penicillins or, after the crystal growth is completed, after the material is cooled or not cooled, the material is discharged and separated, washed, filtered, and dried to obtain the finished product of penicillin.