HU197579B - Process for production of derivatives of cefem carbonic acid - Google Patents

Abstract

According to the present invention there is provided a compound of formula (IV): wherein R4 is C1-C4 alkyl or phenyl, IIZ (R4O) 2P-C (+ -H0NN (IV) (V) c N, yl?) \ T (R * O) 2P-ON n -1-

Description

The present invention relates to a novel process for the preparation of β-lactam derivatives of formula (I). (I) wherein - R ¹ is hydrogen or an alkali metal atom, - R ² represents hydrogen, acetoxymethyl, _(methyl group (Cl-4 alkyl) tetrazolyl-thio-methyl group, [2,5-dihydro- BACKGROUND OF THE INVENTION This invention relates to a novel, improved process for the preparation of cephemcarboxylic acid derivatives of formula (I). The compounds of the present invention are useful antimicrobial agents which are particularly potent against a broad range of microbes such as Streptococcus, Escherichia, Proteus, Shigella, Salmonella, Klebsiella, Serratia, Neisseria and the like. have an effect.

Several methods for preparing semisynthetic β-lactam antibiotics are described in the literature and in the patents. Various β-lactam antibiotics have been prepared by condensation of 7-amino-deacetoxycephalosporanic acid (7-ADCA) or 7-amino-cephalosporanic acid (7-ACA) derivatives; these yielded β-lactam antibiotics to form peptide bonds.

Some methods for preparing the compounds of formula I are known. For example, the amino acids protected by an amino group of formula II, wherein R is an amino protecting group, are converted into their reactive derivatives and then used as acylating agents to acylate 7-ACA, 7-ACDA or derivatives thereof. Reactive derivatives generally include acid halides, reactive esters or reactive amides.

A 102 293/1977, 34795/1978, 68796/1978, 52096/1979. 157,596 / 1979. Japanese Patent Application Laid-Open Patent Publication No. 6,258 and British Patent No. 2,025,933 disclose various methods for the preparation of halides of organic acids of formula II and their use as acylating agents. According to these methods, the organic acids of the formula II are converted into the acid halide with thionyl chloride (SOCl ₂ ), phosphorus pentachloride (PCl ₅ ) or phosphorus oxychloride (POCl ₃ ) and the resulting acid halide. -ADCA or 7-ACA is acylated and the resulting acylated product is deprotected to give compounds of formula (I).

In addition to the complexity of the reaction conditions, the above methods also have the disadvantage of carrying out the necessary steps for protecting the amino group and deprotecting it. In addition, the acid halide is also unstable.

A 102 293/1977., A 95 993/1979. and 152, 488/1981. Japanese Patent Application Laid-Open Publication No. 6,123,123 discloses the synthesis of a reactive ester of an organic acid of formula (II) and the acylation of a 7-ACA, 7-ACDA or a derivative thereof to a compound of formula (I).

The process comprises first preparing the 2-pyridine thioester, the 2-benzothiazole ester or the 1-hydroxybenzotriazole ester of the compound of formula (II) and then acylating 7-ACA, 7-ACDA with this ester. or derivatives thereof to give compounds of formula (I). However, during the preparation of the ester, side reactions take place, the acylation is time consuming and low yielding. Although processes for the preparation of compounds of the formula I are known using acid amides or mixed anhydrides, they have the same problems as those mentioned above. In the above methods, the protecting group R is first applied to the amino group of 2- (2-aminothiazol-4-yl) -2-synmethoxyiminoacetic acid; then the reactive derivative is prepared. e.g. an acid halide or a reactive ester, etc .; acylation is performed and then the protecting group is removed.

A 95593./1979. Japanese Patent Application Laid-Open Patent Application Publication No. 4,102,125 discloses a process for using the 1-hydroxybenzotriazole ester and amide of the compound of formula II. By this method, the esters of formula (VII) and the amides of formula (VIII) are formed in approximately equal proportions.

However, the reactive esters of formula (VII) are highly decomposable, decomposing to the acid of formula (II) and 1-hydroxybenzotriazole. Therefore, it is difficult to isolate the above product and to use it as an acylating agent.

In our long studies, it has been unexpectedly and surprisingly found that when a dialkyl (or diphenyl) thiophosphoric acid chloride of formula (IV) is reacted with a compound of formula (V) in the presence of a base, Compound VIII is reacted with an organic acid of formula (IIa) to selectively yield, in very high yield, the reactive amide of formula (VIII) in solvated form with the solvent used. Reaction of the reactive amide solvate with a compound of formula (III) at room temperature provides the corresponding compound of formula (I) easily and in very high yield.

SUMMARY OF THE INVENTION The present invention relates to a novel acylation process for the preparation of compounds of formula (I) in very high yield, which comprises a dialkyl (or diphenyl) thiophosphonic acid chloride of formula (IV) with 1-hydroxy (V). with benzotriazole;

Potassium (VI) -3197579 is reacted with an organic acid (II) to give a solvate of the reactive amide (VIII) and the resulting amide solvate is reacted with a compound (III).

The process of the invention is illustrated in Scheme 1. In the formulas, R ¹ and R ² are as defined above, R ⁴ is C 1-4 alkyl or phenyl.

The reaction for preparing the dialkyl (or diphenyl) -1-hydroxybenzotriazole thiophosphate (VI) is preferably carried out in solvents such as tetrahydrofuran,,, Ν-dimethylformamide or N, N-dimethylacetamide. Most preferred is tetrahydrofuran. Bases such as triethylamine, trimethylamine or pyridine may be used in the reaction. Most preferred is triethylamine.

The new dialkyl (or diphenyl) -1-hydroxy in formula VI is not isolated from the reaction mixture, but is reacted, inter alia, with a solution of the organic acid of formula Ha. Preferably, a solvent such as Ν, Ν-dimethylformamide or N, N-dimethylacetamide is used to dissolve the organic acid of formula 11a.

The compound of formula (VI) is preferably reacted with an organic acid of formula (IIa) in the presence of a base. The base used in this reaction is, for example, triethylamine, trimethylamine or pyridine. Most preferred is triethylamine. The reaction is usually carried out at room temperature for 1 to 2 hours to give a solvate form of the reactive amide of formula VIII as a precipitate. The subsequent acylation reaction is preferably carried out in a mixed solvent consisting of an aqueous solution of a base and an organic solvent. For example, inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and the like can be used. or organic bases such as trimethylamine or triethylamine. Sodium bicarbonate is preferably used.

The organic solvent used in the process is, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, Ν, Ν-dimethylformamide, N, N-dimethylacetamide or dioxane. Preferred solvents are acetonitrile, acetone, tetrahydrofuran and N, N-dimethylformamide.

In the process of the invention, the compounds of formula (III) are dissolved in a basic solution and an organic solvent is added thereto. The reactive amide solvate (VIII) is added in crystalline form and stirred at room temperature for 1-5 hours. The reaction is quantitative. The organic solvent was then evaporated in vacuo. The resulting aqueous phase was adjusted to pH 4.0 to isolate the 1-hydroxybenzotriazole formed during the reaction, and the aqueous phase was saturated with sodium chloride, and ethyl acetate was added slowly to the saturated aqueous phase and the By adjusting the pH to the isoelectric point, the compound of formula (I) is recovered as a precipitate.

Preferably, 10 to 30 times the amount of water and organic solvent is used for the compound of formula (III). The ratio of water to organic solvent is 2: 1 to 1: 2.

The advantages of the invention compared to the known methods are as follows:

1.) The solvate of the reactive amine of formula (VIII) is prepared in very high yield and in very pure form using the new dialkyl (or diphenyl) -1-hydroxybenzotriazolyl thiophosphate of formula (VI): Compounds of formula VI are prepared by reacting readily available and inexpensive 1-hydroxybenzotriazole with dialkyl (or diphenyl) chlorothiophosphate.

2.) The solvate of the reactive amide of formula (VIII) is very soluble in various organic solvents, which can be acylated homogeneously in a short reaction time with this solvate.

3.) The reactive amide of formula VIII is srv-halide! or, unlike mixed anhydride, it is very stable at room temperature and therefore the solvate of the reactive amide of formula (VIII) is commercially available.

4.) The process of the invention can be carried out at room temperature.

5.) Although the amino group of the organic acid of formula (Ha) is unprotected, the reaction proceeds quantitatively without any side reaction. Therefore, there is no need for the amino group of the compound of formula II to be deprotected or deprotected.

6.) After completion of the reaction, the desired compound is readily isolated from the reaction mixture.

Accordingly, the processes of the present invention can be carried out on simple manufacturing equipment and do not involve any complicated operations at all compared to the known methods. Thus, the present invention provides a novel economical process for the preparation of compounds of formula (I).

The following examples serve only to better illustrate the invention.

Example 1

13.5 g (0.1 mol) of 1-hydroxybenzotriazole are completely dissolved in 80 ml of tetrahydrofuran and 16.8 ml of 0.12 mol of triethylamine and

Diethylthiophosphoric acid chloride (20.8 g, 0.11 mol) was added. Crystalline triethylamine hydrochloride is precipitated as the reaction proceeds. The reaction mixture was stirred at room temperature for 1 hour, then the precipitate was filtered off and washed with 20 ml of tetrahydrofuran.

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The filtrate and washings were combined and added to 100 ml of Ν, Ν-dimethylformamide and

2- (2-Aminothiazol-4-yl) -2-synmethoxyiminoacetic acid (20.1 g, 0.1 mol) in triethylamine (13.9 ml) was added dropwise over 10 minutes. . The reaction mixture was stirred at room temperature for a further 1 hour and then at 0 to 5 ° C for 2 hours, with continuous precipitation. The precipitate was washed with DMF and dried. Yield: 36.0 g of a reactive amide of 1-Ya-syn-methoxyimino-α- (2-a-minothiazol-4-ylacetyl) -benzothiazole-3-oxide (92%). ¹ ): 1730 (amide carbonyl)

NMR (DMSO-d _6, 6 ppm): 2.27 (3H, s, _N-CH3), 2.90 (3H, s, _N-CH3), 3.90 (3H, s, -OCH ₃ ), 7.07 (1H, s, thiazole-H), 7.13 (2H, s, -NH ₂ ), 7.5-8.5 (4H, m, benzotriazole-H), 7, 97 (1H, s, HC-)

SHE

M.p. 156-159 ° C (dec.).

Example 2

The reaction was carried out as in Example 1, but using tetrah, Ν-dimethylformamide (DMF) as the solvent instead of tetrahydrofuran. 34.4 g of 1- [α-synmethoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole-3-oxide are obtained in 88% yield.

The IR and NMR data of the product obtained were the same as in Example 1.

Example 3

The reaction was carried out as described in Example 2, but using diphenylthiophosphoric acid chloride instead of diethyl chlorothiophosphate. 36.4 g of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole-3-oxide DMF solvate are obtained in 93% yield.

The IR and NMR data of the product obtained were the same as in Example 1.

Example 4

The reaction was carried out as in Example 2, but using N, N-dimethylacetamide as the solvent instead of tetrahydrofuran and Ν, Ν-dimethylformamide. 34.4 g of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole-3-oxide DMA solvate are obtained in 85% yield.

IR (KBr, cm ^-1 ): 1730 (amide carbonyl), 1655 (DMA carbonyl),

NMR _(DMSO-d6, his, ppm): 2.05 (3H, s, C- CH _3), 2.30 (3H, s, _N-CH3), 2.95 (3H, s, ll

SHE

-N-CH ₃ ), 3.95 (3H, s, -OCH ₃ ), 7.10 (1H, thiazole-H), 7.20 (2H, s, -NH ₂ ), 7.4-8, 4 (4H, m, benzotriazole-H).

Mp: 157-160 ° C (dec.).

Example 5

To a mixture of water (100 ml) and acetonitrile (200 ml) was added 5.4 g of 7-aminocephalosporanic acid. Sodium bicarbonate (2.4 g) was added and the mixture was stirred at room temperature for 10 minutes until completely dissolved. To the resulting mixture was added 6.40 g of 1- [α-synmethoxy-imino-α- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide DMF solvate prepared in Example 1. and the mixture was stirred at room temperature for 4 hours to complete the reaction. Then acetonitrile was distilled off, the solution was cooled to 0-5 ° C, adjusted to pH 4.0 with 2N hydrochloric acid and stirred for 1 hour to form a precipitate. The mixture was filtered, the filtrate was saturated with sodium chloride, ethyl acetate (120 mL) was added and the pH was adjusted to 2.5 with 2N hydrochloric acid with vigorous stirring. A pale yellow precipitate is formed. The reaction mixture was stirred for 1 hour, filtered and the precipitate was dried. 8.65 g (95%) of 7 - {[2- (2-aminothiazol-4-yl) -2-methoxyimino] -acetamido) -ephephalosporanic acid (cefotaxime) are obtained.

IR (KBr, cm ^-1 ): 1780 (β-lactam carbonyl) NMR (D ₂ O / NaHCO ₃ , 6, ppm): 2.08 (3H, s,

-C-CH ₃ ), 3.53 (2H, d, C ₂ -H), 4.02 (3H, s, -OCH ₃ ), 4.84 (2H, d, 3-CH ₂ -), δ 20 (IH, d, C ₆ -H), 5.82 (IH, d, C _r H), 6.97 (lH, s, thiazole-H).

Example 6

The reaction was carried out as in Example 5, but using an equimolar amount of tetrahydrofuran as solvent instead of acetonitrile. Yield: 8.44 g (93%) of 7 - ([2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido) cephalosporanic acid.

The IR and NMR data of the product obtained were the same as in Example 5.

Example 7

The reaction was carried out as in Example 5, but using an equimolar amount of acetone instead of acetonitrile. 8.26 g (91%)

7 - {[2- (2-Aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} -eephosporanoic acid is obtained.

The IR and NMR data of the product obtained were the same as in Example 5.

Example 8

To a mixture of 100 ml of water and 40 ml of Ν, Ν-dimethylformamide is added 5.44 g of 7-aminocephalosporanic acid, and 2.4 g of sodium bicarbonate are added and the mixture is stirred at room temperature for 10 minutes to dissolve the solid, then cooled to below 10 ° C. To the cooled solution, 7.87 g of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole in 40 ml of Ν, Ν-dimethylformamide was added dropwise. -3-oxide DMF solvate. The solution was stirred at room temperature for 4 hours to complete the reaction.

The Ν, Ν-dimethylformamide solution is extracted twice with 150 ml of ethyl acetate, and the aqueous phase is saturated with sodium chloride. The solution was cooled to 5 ° C, adjusted to pH 4.0 with 2N hydrochloric acid, and filtered to remove insoluble impurities. The filtrate was adjusted to pH 2.5 with 2N hydrochloric acid to give a pale yellow precipitate. The mixture was stirred for 1 hour and then filtered. The resulting precipitate was washed with water and dried. Thus, 7.98 g of 7 - {[2- (2-aminothiazol-4-yl)

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-2-syn-methoxyimino] -acetamido-cephalosporanic acid is obtained.

The product obtained has the same IR and NMR data as in Example 5.

Example 9

The reaction was carried out as in Example 8, but using equimolar amounts of Ν, Ν-dimethylacetamide instead of Ν, Ν-dimethylformamide. 7.96 g (88%) of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} cephalosporanic acid are obtained.

The product obtained has the same IR and NMR data as in Example 5.

Example 10

The reaction was carried out as in Example 5 for 3 hours; 8.10 g of the DMA solvate prepared in Example 5 were used. 8.92 g (98%) of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido) -ephephalosporanic acid are obtained.

The product obtained has the same IR and NMR data as in Example 5.

Example 11 3.28 g of 7-amino- [3- (1-methyl-1H-tetrazol-5-yl)] -thiomethyl-3-cephem-4-carboxylic acid in 2.0 ml of water followed by 2.0 g of sodium hydrocarbonate was added. After stirring for 20 minutes at room temperature, acetonitrile (40 mL) was added and the mixture was cooled to 10 ° C. Then, 4.68 g of 1- [α-synmethoxy-imino-G- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide DMF solvate prepared in Example 1 is added. . The mixture was stirred at room temperature for 1 hour, at which time the mixture was dissolved and the reaction was complete. The solution was evaporated in vacuo and the aqueous phase was treated with water (40 mL), adjusted to pH 3.8 with 2N hydrochloric acid, stirred for 1 hour, and the precipitate was filtered off. The filtrate was saturated with sodium chloride and adjusted to pH 2.7 with 2N hydrogen chloride. The resulting precipitated solution was stirred at 5 ° C for 2 hours, then the precipitate was filtered off and dried. There were thus obtained 4.65 g of 7- ([2- (2-aminothiazol-4-yl) -2-dimethoxyimino] acetamido) -3 - [(1-methyl-1 H) in 91% yield. Tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid (cemenoxime) is obtained.

IR (KBr, cm ^-1 ): 1780 (β-lactam carbonyl) NMR (D ₂ O / NaHCO ₃ , δ): 3.84 (2H, d, C ₂ -H),

4.01 (3H, s, -OCl ₃ ), 4.05 (3H, s, -N-CH ₃ ),

5.20 (1H, d, C ₆ -H), 577 (1H, d, C ₇ -H),

7.01 (1H, s, thiazole-H).

Example 12

The reaction was carried out as in Example 11, but using 40 ml of ethyl acetate instead of acetonitrile. Thus, in a yield of 90%, 4.60 g of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamidoyl-3 - [(1-methyl-1 H- tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid is obtained.

The IR and NMR data of the product obtained were the same as in Example 11.

Example 13

The reaction is all. Example 4 was carried out for 3 hours using 4.05 g of the DMA solvate prepared in Example 5 instead of the DMF solvate. Yield: 94%

4.97 g 7 - {[2- (2-Aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid is obtained.

The IR and NMR data of the product obtained were the same as in Example 11.

Example 14 In a mixture of water (30 ml) and tetrahydrofuran (30 ml), 7-amino-3- (2,5-dihydro-2-methyl-6-hydroxy-5-oxo-triazin-3-yl) -thio methyl 3-cephem-4-carboxylic acid was added followed by 2.79 g of sodium bicarbonate. To the resulting clear solution of pH 8.0-8.2 was 4.68 g of 1- [α-synmethoxyimino-α- (2-a-minothiazol-4-yl) acetyl] benzothiazole-3 oxide DMF solvate was added and the mixture was stirred at 5 ^° C for 1 hour, then the temperature was raised to 25 ° C was stirred for 5 hours. The tetrahydrofuran was then distilled off in vacuo, water (30 ml) was added and the pH was adjusted to 2N with hydrochloric acid.

Adjust to 4.2. The mixture was stirred for 30 minutes and the insoluble material formed was filtered off. The filtrate was saturated with sodium chloride, pH 2N hydrochloric acid

2.9 Adjust to 3.0 and stir the precipitated mixture for 2 hours while maintaining the pH constant. The precipitate is then filtered off and dried. Thus, 7.70 g of 7- (12- (2-aminothiazol-4-yl) -2-synmethoxyimino) -acetamido-3 - [(2,5-dihydro-6) (85% yield) are obtained. -hydroxy-2-methyl-5-oxo-α-triazin-3-yl) thiomethyl] -3-cephem-4-carboxylic acid (ceftriaxone) is obtained.R (KBr, cm ^-1 ): 1780 (β) lactam carbonyl) NMR (D ₂ O / NaHCO ₃ , δ): 3.20 (2H, d, C ₂ -H),

3.62 (3H, s, _N-CH3), 3.95 (3H, s, _-OCH3);

4.21 (2H, d, -S-CH ₂ -), 5.17 (1H, d, C ₆ -H),

5.72 (1H, d, C ₇ -H), 6.95 (1H, s, thiazole-H).

Example 15

The reaction was carried out as described in Example 14, but using tetrahydrofuran instead of 40 ml of acetonitrile. Thus, 4.50 g of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} -3- [(2,5-dihydro-6-) is obtained in 81% yield. hydroxy-2-methyl-5-oxo-aza-triazin-3-yl) -thiomethyl] -3-cephem-4-carboxylic acid is obtained.

The IR and NMR data of the product obtained were the same as in Example 14.

Example 16

The reaction was carried out using 4.05 g of the DMA solvate prepared in Example 5 a

Carried out as in Example 14 for 4 hours. 5.27 g of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} 3 - [(2,5-dihydro-6-) is obtained in 91% yield. Hydroxy-2-methyl-5-oxo-triazin-3-yl-thiomethyl] -3-cephem-4-carboxylic acid is obtained.

The IR and NMR data of the product obtained were the same as in Example 14.

, ϊιΜι

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Example 17 To a mixture of ml of water and 20 ml of tetrahydrofuran was added 1.88 g of 7-amino-3-cephem-4-carboxylic acid followed by 2.0 g of sodium bicarbonate. The solution is cooled to 5 ° C and 3.91 g of 1- [α-synmethoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole-3-oxide are added over 10 minutes. DMF solvate. The mixture was stirred at 5 ° C for 1 hour and then at 25 ° C for 2 hours. Tetrahydrofuran was distilled off in vacuo, water (15 mL) was added, and the mixture was cooled to 5 ° C and adjusted to pH 4.2 with 2N hydrochloric acid. After stirring for 30 minutes, the insoluble material was filtered off, the filtrate was saturated with sodium chloride and the pH was adjusted to 2.8 with 2N hydrochloric acid. The resulting precipitated solution was stirred in an ice bath at constant pH for 2 hours and then filtered. The precipitate was washed with saturated sodium chloride solution and then with chilled water and dried. Yield: 3.48 g (91%) of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] acetamido} -3-cephem-4-carboxylic acid.

IR (KBr, cm ^-1 ): 1780, 1695, 1655.

NMR (DMSO-d, delta): 3.60 (2H, bs, _C2 --H),

3.84 (3H, s, -OCH ₃ ), 5.12 (1H, d, C ₆ -H),

5.84 (1H, d, C ₇ -H), 6.52 (1H, s, 3-H), 6.76 (1H, s, thiazole-H), 7.26 (2H, broad -NH ₂ ),

9.65 (1H, d, -NH-CO).

Example 18

The reaction was carried out as described in Example 17, but using acetone (20 mL) instead of tetrahydrofuran. yield 90%

There was thus obtained 7.40 g of 7 - [[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] acetamido} -3-cephem-4-carboxylic acid.

The IR and NMR data of the product obtained were the same as in Example 17.

Example 19

The reaction was carried out with 4.05 g of the DMA solvate prepared in Example 5 as in Example 17 for 3 hours. 5.27 g of 7 - {[2- (2-aminothiazol-4-yl) -2-syn] is obtained in 94% yield.

of methoxyimino] -acetamido] -3-cephem-4-carboxylic acid is obtained.

The IR and NMR data of the product obtained are the same as in Example 17.

Example 20 Sodium acetate and 8.65 g of 7 - {[2- (2-aminothiazol-4-yl) -2-synmethoxyimino] -acetamido} ceph alosporanoic acid prepared in Example 5. (cefotaxime) is dissolved in 28 ml of methanol. The solution is mixed with 0.4 g of activated carbon and the activated carbon is filtered off and the carbon is then filtered off with charcoal and washed with 7 ml of methanol. The filtrate and the washings were combined and 95 ml of isopropyl alcohol was added dropwise. The mixture was stirred at room temperature for 3 hours. The resulting crystalline product was filtered off and dried to give cefotaxime sodium (94.0%). 162-163 ° C (dec.).

Claims (1)

Patent Claim Point A process for the preparation of compounds of formula I wherein: R ¹ is hydrogen or alkali metal, R ² is hydrogen, acetoxymethyl (C 1-4 alkyl) tetrazolylthiomethyl, [2, 5-Dihydro-6-hydroxy-2- (C 1-4 alkyl) -5-oxo-triazinyl] thiomethyl, wherein a compound of formula IV wherein R ⁴ is 1 -C 4 alkyl or phenyl, is reacted with 1-hydroxybenzotriazole of formula (V) and the resulting compound of formula (VI) wherein R ⁴ is as defined for formula (NV) is reacted with N, N -dimethylformamide or Ν, Ν-dimethylacetamide in a solvent and then acylate a compound of formula (III) wherein R ¹ and R ² are as defined herein with a solvate of the resulting reactive amide (VIII).