HRP940690A2 - Process for the preparation of cefodizime - Google Patents

Description

Cefodisim (HR 221) formula

[image]

(cefodisim)

is an antibiotic whose preparation and good antibiotic activity are known from the literature. It can be obtained by chemical conversion on the carboxyl group of the activated ATS formula

[image]

(ATS)

ATS= 2-(2-amino-thiazol-4-yl)-2-(methoxyimino)-acetic acid with TACS formula

[image]

(TAX)

TACS= 7-amino-3-(4-methyl-5-carboxymethyl-1,3-thiazol-2-yl-thiomethyl)-cef-3-em-4-carboxylic acid. A particularly suitable procedure for the preparation of cephalosporins is described in EP-A 23 453. If it is used for the preparation of cefodisim, in addition to the desired cefodisim, a side product of the order of 5 to 15% is formed. The content of the side product can be reduced by different successive stages of purification, but still it cannot be completely removed from cefodis. In addition, these cleaning procedures (e.g. chromatography, recrystallization) are expensive, because they are long-lasting and significantly reduce the total gain.

That's why they carried out a lot, in order to change the reaction parameters, with the aim of preventing the formation of a side product, such as by varying the ratio of moles, temperature, reaction time, solvent, the base that needs to be added in the given example, the activated agent or with other additions. None of these attempts were successful. The formation of the mentioned secondary product could not be reduced.

When testing further additives, we suddenly found that the addition of a silylating agent to TACS almost completely prevents the formation of a side product.

The invention therefore relates to a process for the preparation of cefodisim formula

[image]

(cefodisim)

indicated by that

(a) first in an organic solvent and in the given example in the presence of a base compound of formula II (ATS)

[image]

in which R-1 represents hydrogen or an amino protecting group and A is a hydrogen atom or an equivalent of an alkali or alkaline earth metal, ammonia or an organic nitrogen base, chemically converted with the compound of formula III

R-SO2-Hal

in which instead of R stands in the given example a substituted alkyl, aryl or aralkyl residue and Hal represents a halogen atom,

(b) in an organic solvent and in the given example in the presence of a base with a compound of formula I (TACS)

[image]

in which A has the above meaning, chemically convert with a silyl agent i

(c) we chemically convert both of the products obtained according to (a) and (b) in their reaction solutions and in the final product of formula I we cleave off the protective group R1 present in the given example.

And besides hydrogen and ammonia, there can also be an equivalent of an alkali metal, such as sodium or potassium, an alkaline earth metal, such as calcium and magnesium, or an organic nitrogen base, such as diethyl-, trimethyl-, triethyl-, methyl-, propyl-, N,N-dimethylethanol- or ethanolamine.

Suitable protecting groups R1 are those described in cephalosporin or peptide chemistry as amino protecting groups, for example those mentioned in EP-A-23 453, p. 3, lines 43 to 63. First of all, let's use in the sense of the invention the compounds, in which instead of R1 is hydrogen. By optional protection of the amino group, we can save two reaction steps (protection, separation), which leads to an even wider increase in profit.

As compounds of formula III, all those described in the literature as suitable for chemical conversion with carboxylic acid, such as methanesulfonyl chloride or tosyl chloride, are considered, whereby an activated carboxylic acid residue -COOSO2-R is probably formed. Compounds that are preferred due to good reactivity and easy availability are compounds such as p-tosyl chloride and also phenylsulfonyl chloride. Furthermore, the preferred compounds are formula III, in which chlorine is used instead of Hal.

The chemical conversion between the compound of formula II and the compound of formula III can be carried out in an anhydrous organic solvent, such as acetone, ethyl acetate, tetrahydrofuran, acetonitrile, carbon tetrachloride, methylene chloride, toluene, dioxane, isopropyl ether, N-methylpyrrolidone, dimethylformamide, preferably in dimethylacetamide at temperatures between around -30 to 0ºC, preferably between -10 and 15ºC.

If we use the compound of formula II in the form of a free acid (A = hydrogen), it is thought to add a base, primarily an organic nitrogen base, such as triethylamine, N,N-dimethylaniline, tributylamine, N-methyl-morpholine, pyridine, picoline or also, for example, sodium or potassium carbonate or bicarbonate, especially triethylamine. The base does not need to be added, if we use the carboxylic acid of formula II in the form of one of the above-mentioned salts.

Further chemical conversion is now performed by chemically converting the compound of formula I (TACS) in an anhydrous organic solvent, such as methylene chloride, dimethylacetamide, methyl tert-butyl ether, methyl isobutyl ketone, butyl acetate or amyl acetate, especially methylene chloride or methyl tert-butyl ether, with about 3 molar equivalents of a silylating agent, preferably with trimethylchlorosilane, in the presence - considering the silylating agent - of an approximately stoichiometric amount of an organic nitrogen base, especially triethylamine, and then converted with a carboxylic acid of formula II, activated by chemical conversion with a compound of formula III.

Instead of trimethylchlorosilane, we can use other silylating agents, such as, for example, bis-trimethylsilyl-acetamide, dichlorodimethylsilane, trichloromethylsilane or N,N-bistrimethylsilylurea, and of these further silylating agents, bis-trimethylsilylacetamide is preferable. A small excess of silylating agent, exceeding 3 molar equivalents, does not harm the conversion.

When using bis-trimethylsilylacetamide or N, N - bis-trimethylsilylurea during silylation, it is not necessary to add a base, because in that case no hydrochloric acid appears, which needs to be bound.

The silylation of the compound of formula I is carried out at temperatures between about 20 to 25º C. We can also let it grow, for example, to around 40º C (boiling point of methylene chloride).

Activated ATS together with silylated TACS should be prepared so that at temperatures between -20 to 0º C, preferably between -10 to -12º C, to the solution of activated ATS and slowly added to the solution of silylated TACS, so that the heat generated by the reaction can be well dissipated. eg in a time interval of 1/4 to 2 hours. After a short subsequent mixing, the reaction mixture is processed in a known manner. So we can, for example, pour it into water, the pH of which we maintain at around 6.0 to 7.5 with the addition of, for example, an organic nitrogen base, especially triethylamine. After separating the phases, the organic phase can then be extracted once more with water in which sodium acetate is dissolved. From the combined organic phases, which we can further clarify in this example, e.g. with activated carbon, adjust the pH to a value of about 2.8 with the addition of a mineral acid, e.g. sulfuric acid, and then we can precipitate cefodisim as a free acid.

If we use a carboxylic acid of formula II with an amino protecting R1, this residue is required before processing in a manner known from the literature.

After drying at a slightly elevated temperature and in a vacuum, we get cefodis acid in a very pure form.

In addition to the above-mentioned unexpected reduction of side products to a content far below 1%, let us also mention that, for example, in embodiments 8 to 12 of the already mentioned EP-A-23 453, reaction temperatures between -70 to -70 -72ºC.

On the contrary, it is possible to carry out the chemical conversion in terms of the invention at temperatures from about -20 to 0ºC, without any deterioration in quality or profit. This fact is very significant for the technical production of cefodis, because it is associated with a shorter retention time and lower cooling capacity.

Example 1

Degree 1

17.5 kg (87.1 moles) of ATS in 52 kg of dimethylacetamide are converted with 8.95 kg (88.6 moles) of triethylamine into the ammonium salt at a temperature of 20 to 22º C and a mixing time of 30 minutes.

Dissolve 12.9 kg (68.0 moles) of p-toluenesulfochloride in 13.2 kg of dimethylacetamide over the course of 30 minutes at 20 to 25ºC, let this solution flow into the triethylammonium salt suspension ATS for 30 minutes at -10 to -14ºC and then for another 2 , we mix for 5 hours.

Degree 2

We suspend 23.7 kg (59.0 moles) of TACS in 212 kg of methylene chloride, let 19.7 kg (181.0 moles) of trimethylchlorosilane flow in at a temperature of 20 to 25ºC, and for 30 minutes at a temperature of 20 to 41ºC (reflux temperature of methylene chloride) add 18.2 kg (180.0 moles) of triethylamine.

After the addition, the solution is quickly cooled to -15ºC and the activated ATS solution, obtained in the first step, is added for 30 minutes at -10 to -12ºC. After 5 minutes of mixing, let the reaction mixture flow into the mixture of 143 l of water and 19.3 kg of triethylamine, while maintaining the pH value between 6 and 7.5. After separating the phases, the methylene chloride phase is extracted once again with 70 l of water, in which 2.2 kg of sodium acetate · 3 H2O is dissolved, and from the combined aqueous phases after clarification with 1.2 kg of activated carbon and 1.2 kg of dicalcium and with the addition of 18% sulfuric acid until we reach a pH value of 2.8, we precipitate cefodisim in the form of free acid. After filtering and drying at 40ºC and 133 mbar, we obtain 30.6 kg of cefodisim with a purity of 96 to 97 surface % according to HPLC analysis.

Example 2

Level 1 (corresponds to the data in example 1.)

Degree 2

23.7 kg (59.0 moles) of TACS are suspended in 212 kg of methylene chloride and 36.0 kg (177.0 moles) of bistrimethylsilylacetamide are added. Stir for 30 minutes at 20 to 25ºC, cool the clear solution to -15ºC and during 30 minutes at -10 to -20ºC add the solution of unactivated ATS, obtained according to step 1. After 5 minutes of mixing, let the reaction mixture flow for 5 to 10 minutes in 143 l of water and at the same time we maintain the pH value with triethylamine between 6.0 and 7.7. After separating the phases, the organic phase is extracted once again with 70 kg of water containing 2.2 kg of sodium acetate 3 H20. Clarify the combined aqueous phases with 1.2 kg of activated carbon and 1.2 kg of dicalcium, and by adding 18% sulfuric acid until a pH value of 2.8 is reached, precipitate the product. After filtering and drying at 40ºC and 133 mbar, we obtain 30.0 kg of cefodisim in the form of free acid with a purity of 95 to 97 surface % according to HPLC analysis.

Claims (14)

1. Procedure for preparation of cefodisim formula [image] (cefodisim) indicated by that, yes (a) first in an organic solvent and in the given example in the presence of a base, the compound of formula II (ATS) [image] in which R1 represents hydrogen or an amino protecting group and A is a hydrogen atom or an equivalent of an alkali or alkaline earth metal, ammonia or an organic nitrogen base, chemically converted with the compound of formula III R-SO2-Hal in which instead of R stands in the given example a substituted alkyl, aryl residue and HaL represents a halogen atom, (b) in an organic solvent and in the given example in the presence of a base with a compound of formula I (TACS) [image] in which A has the above meaning, chemically convert with a silyl agent i (c) we chemically convert both of the products obtained according to (a) and (b) in their reaction solutions and in the final product of formula I we cleave off the protective group R1 present in the given example. 2. The process according to claim 1, characterized in that in the compound of formula III, p-tolyl or phenyl is used instead of R and Hal is chlorine. 3. Process according to claim 2, characterized in that instead of R stands p-tolyl. 4. Process according to claims 1 to 3, characterized in that in the compound of formula II (ATS) instead of R1 and A there are hydrogens. 5. The method according to claims 1 to 5, characterized in that the solvent acetone, dimethylacetamide, ethylacetate, tetrahydrofuran, acetonitrile, carbon tetrachloride, methylene chloride, toluene, dioxane, isopropyl ether, N-methylpyrrolidone, dimethylformamide is used in step (a). 6. The method according to claim 5, characterized in that the solvent is dimethylacetamide. 7. Process according to claims 1 to 6, characterized in that silyl is trimethylchlorosilane, dichlorodimethylsilane, trichloromethylsilane, bis-trimethylsilylacetamide or N,N-bis-trimethylsilylurea. 8. The method according to claim 7, characterized in that the silylating agent is trimethylchlorosilane. 9. The method according to claims 7 to 8, characterized in that we use 3 molar equivalents of the silylating agent in relation to TACS. 10. The process according to claims 1 to 8, characterized by the fact that methylene chloride, dimethylacetamide, methyl tert-butyl ether, methyl isobutyl ketone, butyl acetate or amyl acetate is used as a solvent in step (b). 11. The method according to claim 9, characterized in that the solvent is methylene chloride or methyl tert-butyl ether. 12. The process according to claims 1 to 10, characterized in that the base, which is added between the individual stages of the process, is triethylamine. 13. The process according to claims 1 to 11, characterized in that we carry out the chemical conversion of process step (a) at temperatures between about -30 to 0ºC. 14. The process according to claims 1 to 12, characterized in that we carry out the chemical conversion of process step (b) at temperatures between about -20 to 0ºC.