Receiving cefotaxime and sodium salt of cefotaxime


C07D501/24 - with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
C07D501/06 - Acylation of 7-aminocephalosporanic acid

 

(57) Abstract:

The invention relates to a method for Cefotaxime formula I by reacting acetone compounds of the formula II with the compound of the formula III and subsequent, if necessary, converting the compounds of formula I in the presence of a source of sodium ions in a mixture of acetone and water in the sodium salt of Cefotaxime in the form of rounded agglomerates with a bulk density of 0.2-0.6 g/ml or in the form of needle crystals. The technical result - receiving Cefotaxime and its sodium salt, high purity, and efficiency of the process. 3 s and 5 C.p. f-crystals.

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This invention relates to a method of producing a cephalosporin, namely Cefotaxime formula

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Cefotaxime is a third-generation cephalosporin with a wide range and is one of the most important parenteral antibiotics. It is usually administered in the form of its sodium salt.

In accordance with methods known in obtaining Cefotaxime, enter the appropriate side group, a protected or unprotected amino group of 7-ACA of formula

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At the next stage Cefotaxime in the form of the free acid can be pravom the introduction of side groups in the 7-ACA is its interaction with reactive tieferen (MAI) formula

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In accordance with this method there is no need to protect the amino group of 2-aminothiazolyl group, and the acylation reaction takes place with high yield without significant adverse reactions. This method using the active ester was first described (EP-0037380).

The known method (EP-0037380, examples 1 and 2) receipt of Cefotaxime in the form of the free acid, is as follows:

a) similarbut 7-ACA of formula II with N,O-bestemmelser-cetamide;

b) acelerou Siciliano 7-ACA using MAI formula III in dichloromethane;

C) extracted with a mixture of water/potassium bicarbonate;

g) re-extracted with Cefotaxime in the form of the free acid with a mixture of ethyl acetate/butanol;

d) dried and evaporated organic containing Cefotaxime, phase and washed with diethyl ether.

This process is economically feasible, however, the use of dichloromethane in an industrial scale is undesirable for environmental reasons, especially for the production of pharmaceuticals, and the use of diethyl ether should be avoided for reasons of process safety. Known (EP-0037380) treating the reaction mixture is quite complex.

It is known (US 5336776 or Ivate the solvate.

Obtaining the sodium salt of Cefotaxime from MES Cefotaxime happens with grip solvent, which leads to the formation of MES during the formation of sodium salt. The result is an undesirable contamination of the sodium salt solvents used at the stage of acylation, as well as the problems associated with recovery of the solvents used during the formation of salt.

In accordance with the invention was found simple, environmentally convenient and economical way to get Cefotaxime, which eliminates the disadvantages of known methods and provides Cefotaxime and its sodium salt exceptional purity, stability and with high yields.

In the present invention proposes a method of receiving Cefotaxime formula

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the interaction of the compounds of formula

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with the compound of the formula

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in acetone.

The method according to the invention can be implemented as follows.

The compound of formula II acelerou compound of formula III, using as solvent acetone, possibly in the presence of water. Preferably using a mixture of acetone/water. The concentration of reagents in alleluya of reaction from the concentrations of reagents used in water and acetone, although it is known that Cefotaxime is practically insoluble in water and/or acetone. The outputs can be reduced by dilution of the reaction mixture. Thus, this reaction can be conducted at high concentration. The optimal outputs can be obtained, if grams of 7-ACA using approximately 3 to 6 ml, for example from 3 to 5, in particular from 3.1 to 4.5 ml of acetone and from about 0.1 to 0.3, for example from 0.1 to 0.25, in particular from 0.13 to 0.18 ml of water.

The ratio of water:acetone may be such that the solution get in the presence of a base, for example from about 8:1 to 45:1, in particular from 10: 1 to about 35:1.

The acylation can be conducted in the usual way.

In one embodiment the invention is 7-ACA of formula II may be suspended in a mixture of acetone and water in the presence of MAI formula III in the presence of a base. Acceptable reasons include tert-(C1-C8)bonds alkylamines, for example triethylamine, N-ethyldimethylamine, picoline, N-substituted morpholine; or an inorganic base such as sodium hydroxide, sodium bicarbonate or sodium carbonate or potassium analogues. The ratio of base and compounds of formula II may be from about 1:1 to 1:2, for example 1:1; 1: 1,2; 1:1,5. Aspect] is decisive and can be for example, in the interval between 0 and 50oC, in particular between 10 and 20oC. After completion of the reaction, which can be determined in the usual way, for example chromatographic add acid. Acceptable acid include inorganic acid such as hydrochloric acid or organic acid, such as methanesulfonate acid or benzolsulfonat or toluensulfonate acid. Crystal Cefotaxime get in the form of the free acid of formula I. If appropriate, for example, to improve the confusion, to a suspension of crystals before allocating Cefotaxime, you can add an additional amount of acetone or a mixture of water/acetone.

To obtain the sodium salt of the compounds of formula I, the method includes the following stages:

1) the interaction of the compounds of formula II with the compound of the formula III in acetone;

2) the conversion of compounds of formula I, obtained in stage 1), in the presence of a source of sodium ions in acetone.

The compound of formula I, obtained in stage 1), can be selected.

In addition, according to the invention can be obtained sodium salt of Cefotaxime formula

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in the result of the interaction of 7-ACA of formula II with the compound of the formula III in ro basis or tert-(C1-C8the alkylamine) and conversion of compounds of formula I to compound of formula Ia in a solvent composed of a mixture of acetone and water, in the presence of a source of sodium ions.

The transformation can be carried out in the usual way. In one embodiment of the invention, the transformation is carried out in a solvent similar to obtaining the compounds of formula I, namely Cefotaxime in the form of the free acid can be suspended in acetone, in particular in a mixture of acetone and water, in the presence of sodium ions. The ratio of acetone/water itself for the formation of salts is not determinative.

The source of sodium ions include, for example, sodium salt of carboxylic acid, such as sodium acetate, sodium salt dietramszell acid or 2-ethylhexanoate, sodium or inorganic sources of sodium, such as sodium hydroxide, sodium bicarbonate or sodium carbonate. Sodium ions may be present in an equivalent amount relative to the carboxyl group of Cefotaxime or in excess, for example in a ratio of from 1:1 to 1:2, in particular 1: 1 or 1:1.5 to 1:1,2. After optional filtration of the reaction mixture can be added seed crystals. To achieve completeness kristallwei. Crystallization can be carried out, for example, at temperatures between 0oand 50oC. To complete the crystallization slurry of crystals may be further cooled before allocating product. The allocation of the sodium salt of Cefotaxime may be carried out in the usual way.

The advantages of this method compared to the known (EP-0037380):

- Receiving Cefotaxime and obtaining the sodium salt of Cefotaxime may be carried out in the same solvent.

Traces of acetone sodium salt of Cefotaxime physiologically acceptable.

- You can do without sililirovanie.

- Excluded extraction.

Thus, the method according to the invention is a simple method of obtaining sodium salt of Cefotaxime formula I without special techniques, requiring the introduction of protective groups and without extraction, namely, crystallization of Cefotaxime may be carried out directly in the reaction vessel. You only need one organic solvent, acetone, which is easy to recover. In addition, the quality obtained by the proposed method Cefotaxime and sodium salt of Cefotaxime is excellent. Therefore, the method according IO sodium salt of Cefotaxime, obtained by the method according to the invention, may have a different form (macroscopic) crystals. The first crystals appear in the form of fine needles. After completion of crystallization of the sodium salt of Cefotaxime may be in the form:

(1) rounded agglomerates,

(2) homogeneous needles

(3) a mixture of needles and rounded agglomerates.

The crystal form may depend on the conditions of crystallization, such as time adding acetone at the stage of crystallization (shortened the time of addition can lead to the formation of rounded agglomerates), the ratio of acetone/water (reduction of quantity of water can lead to the formation of rounded agglomerates), number of seed crystals (reduction of quantity of seed crystals can produce a mixture of small needle-shaped crystals and small rounded agglomerates), form seed crystals (use needle-shaped crystals as seed crystals can produce a sodium salt of Cefotaxime in the form of rounded agglomerates; application of known crystals, such as, for example, the crystals Claforanas the seed crystals can produce a sodium salt of Cefotaxime in the form of needles). In the condition, and in terms of, in particular, example 8 sodium salt of Cefotaxime are mainly in the form of needle crystals. Known crystals of sodium salt of Cefotaxime, for example commercially available as a product Claforanturns out , are a mixture of primary crystals (mainly in the form of fragments), which are different from the tiny needles and agglomerates having sharp edges. The shape of the crystals determines light micrograph.

Sodium salt of Cefotaxime in the form of rounded agglomerates or in the form of needles, or a mixture of rounded agglomerates and needle is new and useful.

According to the invention offers the sodium salt of Cefotaxime formula I in the form of rounded agglomerates, and sodium salt of Cefotaxime formula I in the form of needle crystals.

Bulk density of rounded agglomerates, which can be obtained according to the invention (defined according to the European Pharmacopeia), can vary, for example, from 0.23 to 0.5 g/ml (Claforan: 0,46 g/ml). Their bulk density is preferably more than 0.2 g/ml and less than 0.65 g/ml, in particular less than 0.6 g/ml, mainly less than 0.55 g/ml bulk density of known crystals, for example Clafora in the European Pharmacopeia, after 2500 taps of the sample weight, for example 10, the Density increases, but becomes constant after about 2500 taps.

Mainly proposed according to the invention the sodium salt of Cefotaxime formula I in the form of rounded agglomerates have a bulk density of 0.2 g/ml to 0.6 g/ml

Sodium salt of Cefotaxime obtained in accordance with the present invention can be applied similarly to the known salts Cefotaxime and enter it in the same doses and in the same way that the famous salt of Cefotaxime.

Sodium salt of Cefotaxime in the form of rounded agglomerates in the form of needle-shaped crystals has better fluidity in comparison with the known crystals, such as crystals Claforan. Known crystals, such as crystals Claforanusually stick to the walls of the glass container, which is not characteristic of rounded agglomerates and needle-like crystals obtained according to the present invention.

In the following examples, which should more fully illustrate the invention within its scope, all temperatures are given in degrees Celsius.

Abbreviations:

7-ACA:

The compound of formula II

Oxigenoterapia] -8-oxo-5-thia-1-azabicyclo [4,2,0] Oct-2-ene-2-carboxylic acid (compound of formula (I)

Sodium salt of Cefotaxime:

Sodium salt of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2- (2-amino-1,3-thiazol-4-yl)-2-methoxykynuramine] -8-oxo-5-thia-1 - azabicyclo[4,2,0]Oct-2-ene-2-carboxylic acid

The content of Cefotaxime or sodium salt of Cefotaxime determined using ghvd.

Example 1

Getting Cefotaxime

of 54.4 g of 7-ACA is suspended in a mixture of 20 ml of water and 60 ml of acetone. Add at room temperature of 30.7 ml of triethylamine for about 10 minutes. The solution is formed in approximately 30 minutes Add 72,7 g MAI and another 120 ml of acetone. After 1.5 hours the original products are not detected. Add for about 10 minutes, concentrated hydrochloric acid to a total volume of 18.3 ml.

After about 5 minutes is the crystallization of Cefotaxime in the form of the free acid. The suspension of crystals is stirred for 30 minutes at room temperature and the pH adjusted to pH 3.5 with additional quantities of hydrochloric acid.

Is added dropwise within 30 min to 400 ml of acetone and stirred the mixture for 1 hour. Is separated by filtration of the crystalline Cefotaxime in the form of the free acid and dry it in a vacuum drying chamber in the Example 2

Obtaining the sodium salt of Cefotaxime

40 g of Cefotaxime in the form of the free acid are suspended in a mixture of 40 ml of water and 60 ml of acetone. Add 12 g of three-hydrate of sodium acetate. Get the solution and filtered. The filter layer is washed with a mixture of 3 ml of water and 15 ml of acetone two portions. In the combined filtrates at 25oC add 0.4 g of the seed crystals. The mixture is stirred for 1 hour.

Slow crystallization of sodium salt of Cefotaxime. Dropwise within 3 hours add 600 ml of acetone and stirred suspension at the above temperature for 30 minutes. Crystalline sodium salt of Cefotaxime is separated by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40oC. Output: 36,6, the Content of sodium salt of Cefotaxime: 95,9%. Water content: 3.8 per cent.

Example 3

Getting Cefotaxime

Suspended 228,3 g of 7-ACA in 720 ml of acetone. The suspension is mixed with 30 ml of water and cooled to 0-2oC. Add approximately 2 minutes to 112.4 ml of N-ethyldimethylamine. The mixture is stirred at this temperature to obtain a clear solution (about 30 minutes). Add 296,5 g MAI, the reaction mixture is heated to the 15FL already not detected. Added dropwise over 5 minutes a solution of 207,7 g monohydrate p-toluensulfonate acid in 300 ml of acetone. In the reaction mixture is injected seed of 1 g of seed crystals and heated to 20oC. the Resulting crystal suspension is stirred for another 3 h at the same temperature. Crystal Cefotaxime in the form of the free acid is separated by filtration, washed with acetone and dried in a vacuum drying chamber at 40oC. Output: 301,0, the Content of Cefotaxime: 91,7%. Residual solvent: acetone 7,8%.

Example 4

Getting Cefotaxime

228,3 g of 7-ACA suspended in 720 ml of acetone. The suspension is mixed with 30 ml of water and cooled to 0-2oC. for about 2 minutes add 134 ml of triethylamine. The mixture is stirred at this temperature to obtain a clear solution (about 30 minutes). Add 296,5 g MAI. The reaction mixture is heated to the 15oC and stirred at this temperature. After about 30 minutes to get the solution. After 4 h the original products are not detected. Add portions over about 5 minutes 191,7 g hard monohydrate p-toluensulfonate acid. The internal temperature rises to 20oC and the mixture continued to stir. In tlaut 2 g of seed crystals and continue stirring at the same temperature for 2 hours. The suspension of crystals is cooled to 10oC and stirred at this temperature overnight. The product is separated by filtration, washed with acetone and dried in a vacuum drying chamber at 40oC. Output: 341,4, the Content of Cefotaxime: 94,1%. Residual solvents: acetone, or 6.6%, water of 0.5%.

Example 5

Getting Cefotaxime

The reaction is carried out analogously to example 4, but instead 191,7 g monohydrate p-toluensulfonate acid is used 177,2 g benzosulfimide acid. Output: 308,8, the Content of Cefotaxime: 93,6%. Residual solvents: acetone to 7.2%.

Example 6

Getting Cefotaxime

The reaction is carried out analogously to example 4, but using 92,3 g methanesulfonic acid instead 191,7 monohydrate p-toluensulfonate acid. Output: 323,9, the Content of Cefotaxime: 93,7%. Residual solvents: acetone 7,7% water and 0.6%.

Example 7

Obtaining the sodium salt of Cefotaxime

12 g of the three-hydrate of sodium acetate dissolved in 30 ml of water. To the solution was added with stirring 150 ml of acetone and 40 g of Cefotaxime in the form of the free acid. After about 10 min solution is formed. This solution is filtered through the filter layer and then through a sterile filter. The filters are washed with a mixture of 6 ml is stirred for 30 minutes. Sodium salt of Cefotaxime partially crystallizes. To complete crystallization within 3 hours added dropwise 550 ml of acetone and stirring is carried out at 20oWith advanced within 30 minutes. Sodium salt of Cefotaxime is separated by filtration, washed with acetone and dried at 40oC in a vacuum drying chamber during the night. Crystal Cefotaxime sodium mainly in the form of rounded agglomerates get in fluid form having a bulk density less of 0.68 g/ml Yield: 38,8, the Content of sodium salt of Cefotaxime: 95,9%. Residual solvents: acetone, 0.4%, and water of 4.0%.

Example 8

Obtaining the sodium salt of Cefotaxime

6 g of the three-hydrate of sodium acetate dissolved in 20 ml of water. To the stirred solution was added 40 ml of acetone and 20 g of Cefotaxime in the form of the free acid. The mixture is cooled to 0oC. the Solution formed within 2-5 minutes. The solution is filtered through the filter layer, then through a sterile filter. The filters are washed with chilled mixture of 3 ml of water and 15 ml of acetone. In the filtrate make a seed crystal of 0.2 g of the seed crystals (Claforan) and heated to 20oC. This mixture is stirred for 60 minutes. Sodium salt of Cefotaxime is Cetona and stirring is continued at 20oEven within 30 minutes. Sodium salt of Cefotaxime is separated by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40oWith and for 1.5 hours in a stream of dry nitrogen gas at 70oC. Get crystal Cefotaxime sodium mainly in the form of needle crystals. Output: 18,7, Content, sodium salt of Cefotaxime: 97,9%. Residual solvents: acetone 0,36%, water of 1.4%.

1. The way to get Cefotaxime formula I

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by interacting in acetone compounds of formula II

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with the compound of the formula III

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followed, if necessary, converting the compounds of formula I to compound of formula I in salt form.

2. The method according to p. 1, characterized in that the interaction is carried out in the presence of a base.

3. The method according to p. 1 or 2, characterized in that the compound of the formula I is converted into the sodium salt of the compounds of formula I in the presence of a source of sodium ions in acetone.

4. The method according to any of paragraphs.1 to 3, characterized in that the interaction is carried out in the presence of water.

5. The method according to p. 3, characterized in that it comprises a stage a) of the interaction of the compounds of formula II, as defined in UB>8)of the alkylamine in a mixture of acetone and water; b) the allocation of the compounds of formula I; C) conversion of the compounds of formula I in the presence of a source of sodium ions in a mixture of acetone and water, and d) excretion of sodium salt of compounds of formula I.

6. The sodium salt of the compounds of formula I, as defined in paragraph 1, in the form of rounded agglomerates.

7. Sodium salt under item 6, characterized in that it has a bulk density of 0.2 to 0.6 g/ml

8. The sodium salt of the compounds of formula I, as defined in paragraph 1, in the form of needle crystals.

 

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