KR960011779B1 - Novel process for preparing crystalline hydrate of cephalosporin - Google Patents

Abstract

The crystalline cephtazidim bishydroiodide monohydrate of formula(I') are prepared by reacting 3-acetoxymethyl cephalosporin compd. of formula(II) with pyridine in the presence of trimethyliodosilane of formula(III), and reacting compd. of formula(I') with 2-3eq. base. In formula, R1,R2 and R3 are alkyl group of C1-C4.

Description

New preparation method of cephalosporin crystalline hydrate

The present invention relates to a novel process for the preparation of crystalline ceftazidime pentahydrate.

Ceftazidime has the chemical name (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2-syn- (2-carboxyprop-2-oxyimino) acetamido]- Known antibiotics, 3- (1-pyridiniummethyl) -3-cepem-4-carboxylate, as described in British Patent Specification No. 2025398, containing a broad spectrum of antimicrobial activity, particularly Pseudomonas strains. It is known to show excellent antibacterial activity against negative bacteria.

A conventional method for preparing ceftazidime is described in British Patent Specification No. 2025398. According to this method, an appropriate 7-aminocephalosporin is acylated with a compound capable of introducing a preformed 7-substituent, or by reacting 3-acyloxymethyl or 3-halomethyl cephalosporin with a nucleophile (pyridine). Ceftazidime can be prepared by modifying the 3-position and subjecting it to depilation if necessary.

When antibiotics such as ceftazidime are formulated into injections, physical properties such as water solubility and storage stability become important factors. Accordingly, efforts have been made to prepare ceftazidime in a desirable form in terms of water solubility and storage stability, and as a result, it has been confirmed that the ceftazidime is prepared in a hydrate form, particularly pentahydrate, to provide storage stability suitable for injection. .

Crystalline stable ceftazidime pentahydrate has been widely used in formulating as an injection because of its excellent storage stability since it was first described in British Patent Specification No. 2063871A, and thus, research into its preparation method is actively underway. For example, in British Patent No. 2,063,871A, ceftazidibis bishydrochloride is prepared by reacting double-blocked ceftazid solvate with formic acid and hydrochloric acid, and reacting the base to pH 6.5 to 4.2 to adjust ceftazide. A method for preparing dim pentahydrate is described and represented by the scheme below.

In addition, Korean Patent Publication No. 87-829 discloses a ceftazidime bishydrobromide α-monohydrate obtained by reacting a double-blocked ceftazidime with formic acid and HBr, and reacted with a base to adjust the pH to 3.5 to 4.0. A method for preparing dim pentahydrate is described.

European patent specification 0179546 A ₂ describes a process for preparing ceftazidime pentahydrate, which accordingly reacts a double-blocked ceftazidime with formic acid and hydrochloric acid to form a biphasic system and then the aqueous layer without separation of the intermediate. The pH of the mixture is adjusted to about 3.5 to 4.5 to crystallize ceftazidime pentahydrate.

On the other hand, in European Patent Specification No. 0267427 A ₁ and WO 88-02752, hydrochloric acid is applied to a single blocked ceftazidime to form a solution, followed by direct base action to form ceftazidime pentahydrate, or an intermediate. As an example, a method of preparing ceftazidime pentahydrate by isolating crystalline ceftazidime bishydrochloride and then crystallizing by reacting a base therein is described.

European Patent Specification No. 0187450 A ₂ describes a method for purifying ceftazidime containing impurities, which accordingly adjusts the pH of the solution containing ceftazidime to 5.5 to 6.5 and then adds acid to the pH 4.0 to 4.7. A method for obtaining crystalline ceftazidime pentahydrate by controlling with is described.

According to the above methods, in order to prepare ceftazidime pentahydrate, double or single-blocked ceftazidime is deblocked to prepare ceftazidime bishydrochloride or ceftazidime bishydrobromide as an intermediate, and then a base is applied thereto. Or a method of crystallization by adding a base directly to the deblocked reaction solution.

However, when the ceftazidime pentahydrate is prepared according to the above methods, the yield and yield are low as 60 to 80% because of the need for blocking and deblocking reactions and the overall reaction process, and ceftazidime bishydro as an intermediate. Since chloride or ceftazidime bishydrobromide did not provide satisfactory results in terms of storage stability, development of improved methods has been required.

Accordingly, the present inventors have conducted a long-term continuous research, and then reacted 3-acetoxymethyl cephalosporin compound of formula (II) with pyridine of formula (IV) in the presence of trialkyliodine silane of formula (III). By producing a ceftazidime bishydroiodide monohydrate compound of formula (I ') and reacting the base with the resulting intermediate compound (I'), the crystalline ceftazidime pentahydrate of formula (I) is obtained in high yield and It has been found that high purity can be obtained and the present invention has been completed.

(Ⅰ ')

In the above formula, R ₁ , R ₂ and R ₃ are each independently an alkyl group having 1 to 4 carbon atoms.

Hereinafter, the present invention will be described in detail.

In the first step of the process according to the invention, the intermediate compound of formula (I ′) is produced by suspending the starting material of formula (II), the compound of formula (III) and the pyridine of formula (IV) in a suitable solvent. Let's do it. The trialkyliodinesilanes of formula (III) may optionally contain other silylating agents, such as bistrimethylsilyl acetamide (BSA), bistrimethyl silyltrifluoro acetamide (BSTFA), hexamethyldisilazane (HMDS). ) Or a mixture with bistrimethylsilylurea and the like. In this case, the compound of formula (II) may first be reacted with the above-mentioned silylating agent in a suitable solvent, followed by addition of the compound of formula (III) and pyridine of formula (IV) to carry out the reaction.

The 3-acetoxytilcephalosporin compound of formula II used as a starting material in the method of the present invention is a known compound and can be prepared and used according to the method described in Korean Patent Publication No. 82-256.

Solvents used in the first step of preparing the compound of formula (I ′) include methylene chloride, chloroform, 1,2-dichloroethane, and the like, and most preferably, methylene chloride is used.

The reaction is usually carried out at a temperature of 5 ° C. to 80 ° C., most preferably at 40 to 45 ° C.

In the first stage reaction, the compound of the general formula (III) and the pyridine of the general formula (IV) are preferably used in the amount of 1 to 8 equivalents based on 1 equivalent of the compound of the general formula (II), and the silylating agent is required. Therefore, it is preferable to use 1 to 6 equivalents.

The reaction is preferably carried out for 5 hours to 3 days. In the present invention, the carboxyl group deblocking reaction is generally carried out simultaneously with the 3-position substitution reaction in the in situ, but in order to shorten the reaction time, the reaction may be performed by additionally adding hydroiodic acid.

After the reaction is completed, the resulting compound of formula (I ′) can be obtained by distillation and concentration of the reaction solution and crystallization by adding a solvent in a conventional manner. The crystallization solvent used at this time is acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, ethyl acetate, ethanol, isopropyl alcohol or the like, or a mixed solvent thereof is preferred. In order to obtain a more pure compound of formula (I '), it is preferable to repeat the crystallization process 2-3 times.

In the first step of the process according to the invention, the degree of production is the ceftazidime bishydroiodide monohydrate of formula (I ′), which is a novel compound with excellent storage stability, and which is the same as the applicant. The target substance of the application.

In a second step of the process according to the invention, the compound of formula (I ') is treated with a base to produce ceftazidime pentahydrate of formula (I). This reaction can be carried out by dissolving the compound of formula (I ') in distilled water or a mixed solvent of distilled water and a water miscible organic solvent, and then neutralizing by adding a base to the resulting solution. The organic solvent used at this time is preferably methanol, ethanol, isopropanol, acetone, tetrahydrofuran and the like.

In the second stage reaction, sodium hydroxide, calcium hydroxide, sodium hydrogen carbonate, sodium carbonate, triethylamine, pyridine, ammonia water, tetra n-butyl ammonium hydroxide, and the like can be used. Is most preferably used. In particular, when the reaction is carried out in distilled water-organic solvent system using tetra n-butyl ammonium hydroxide as a base, the target substance can be isolated in high yield (90% or more) and high purity (98% or more) without by-products. There is an advantage that it can.

In this reaction, the base is used in a ratio of 1 to 10 equivalents, preferably 2 to 3 equivalents, to 1 equivalent of the compound of formula II.

When the reaction is complete, the reaction solution may be cooled, the reaction solution may be cooled, or a small amount of seed may be added to crystallize the product and then separated to obtain pure crystalline ceftazidime pentahydrate.

The present invention prepares ceftazidime pentahydrate by using the crystalline ceftazidime bishydroiodide monohydrate of structural formula (I '), which has excellent storage stability as compared to the existing methods, and especially as a base. The use of tetra n-butyl ammonium hydroxide has the advantage that the desired material can be prepared in high purity of at least 98% and at least 98% as compared to the existing methods.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited thereto.

Example 1

In a nitrogen atmosphere, 60 ml (0.42 mol) of trimethyl iodine silane and 25 ml (0.31 mol) of pyridine were added to 700 ml of anhydrous methylene chloride, and it stirred at room temperature for 30 minutes. To this solution was added 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] -3-acetoxy 30 g (0.051 mol) of methyl-3-cepem-4-carboxylic acid are added and refluxed under heating for 48 hours. The reaction solution was cooled to room temperature, the resulting solid was filtered off, and then, 1000 ml of methyl ethyl ketone was added to the filtrate, and 20 ml of methanol-purified water 1: 1 solution was slowly added dropwise with stirring. After stirring for 1 hour, the solid is filtered and the resulting solid is dispersed in 500 ml of methylethylketone and stirred for 18 hours. The resulting crystals were filtered, washed with 100 ml of methyl ethyl ketone and dried in vacuo to give 40.1 g (yield: 95%) of the desired compound, crystalline ceftazidime bishydroiodide monohydrate, as pale yellow crystals.

Melting Point (℃): 166 ℃ (Decomposition)

Elemental Analysis (as C ₂₂ H ₂₂ N ₆ O ₇ S ₂ · 2Hl · H ₂ O)

Calculated (%): C; 32.21, H; 3.19, N; 10.24

Found (%): C; 32.35, H; 3.05, N; 10.12

Water (Karl Fisher): 2.40%

IR (KRr): 1544, 1688, 1698, 1784cm ^-1

¹ H-NMR (DMSI-d ₆ ): ppm (δ) = 1.46 (s, 6H), 3.52 (m, 2H), 5.25 (d, 1H, J = 5.5Hz), 5.60 (m, 2H), 5.82 (m, 1H), 6.90 (s, 1H), 6.80 to 8.60 (broad s, 7H), 8.20 (m, 2H), 8.64 (m, 1H), 9.06 (d, 2H, J = 6.0 Hz), 9.60 (d, 1H, J = 9.0HZ)

Example 2

Under a nitrogen atmosphere, 300 ml (0.36 mol) of 1.0M trimethyliodine silane and 25 ml (0.31 mol) of pyridine were added to 400 ml of anhydrous methylene chloride, followed by stirring at room temperature for 30 minutes. To this solution was added 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] -3-acetoxy 30 g (0.051 mol) of methyl-3-cepem-4-carboxylic acid are added and refluxed under heating for 5 hours. After cooling the reaction solution to room temperature, the resulting solids are removed by filtration and the filtrate is distilled under reduced pressure. 30 ml of formic acid and 15 ml of 55% hydroiodic acid were added to the residue, followed by stirring while maintaining the temperature at 30 ° C for 3 hours.

1000 ml of methyl ethyl ketone was added to the solution, stirred for 1 hour, the solution was decanted, and 1000 ml of methyl ethyl ketone was further added, followed by stirring for 18 hours. The resulting solid was filtered and dried under reduced pressure to give 40.5 g (yield: 96%) of crystalline ceftazidime bishydroiodide monohydrate as a pale yellow crystal.

Elemental Analysis (as C ₂₂ H ₂₂ N ₆ O ₇ S ₂ · 2Hl · H ₂ O)

Calculated (%): C; 32.21, H; 3.19, N; 10.24

Found (%): C; 32.18, H; 3.24, N; 10.35

Moisture (Karl Fischer): 2.50%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 1.

Example 3

7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] in 200 ml of anhydrous methylene chloride under nitrogen atmosphere. Suspend 15 g (0.025 mol) of -3-acetoxymethyl-3-cepem-4-carboxylic acid, add 6.5 ml of hexamethyldisilazane and 1.3 ml of 0.1M trimethyliodosilane, and reflux under heating for 12 hours. . After the reaction solution was cooled to room temperature, 5.2 ml (0.064 mol) of pyridine and 51 ml of 1.0 M trimethyliodine silane were added, and the mixture was heated to reflux for 3 hours. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and 30 ml of formic acid and 15 ml of 55% hydroiodic acid were added to the residue, followed by stirring while maintaining the temperature at 30 ° C for 3 hours.

500 ml of methyl ethyl ketone was added to the reaction solution, the mixture was stirred for 1 hour, the solvent was decanted, and 500 ml of methyl ethyl ketone was added thereto, followed by stirring at room temperature for 18 hours. The resulting crystals were filtered and dried under reduced pressure to give 19.0 g (yield: 90%) of crystalline ceftazidime bishydroiodide monohydrate as a pale yellow crystal.

Elemental Analysis (as C ₂₂ H ₂₂ N ₆ O ₇ S ₂ · 2Hl · H ₂ O)

Calculated (%): C; 32.21, H; 3.19, N; 10.24

Found (%): C; 32.05, H; 3.42, N; 10.08

Moisture (Karl Fisher): 2.30%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 1.

Example 4

(1) To 130 ml of anhydrous methylene chloride under nitrogen atmosphere, 120 ml of 1.0M trimethyliodine silane and 8.5 ml (0.105 mol) of pyridine are added and stirred at room temperature for 30 minutes. To this solution was added 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] -3-acetoxy 10 g (0.017 mole) of methyl-3-cepem-4-carboxylic acid is added and then refluxed under heating for 1 hour.

After cooling the reaction solution to room temperature, the resulting solids were removed, and the filtrate was added dropwise with 300 ml of methyl ethyl ketone and 8 ml of methanol was added dropwise while stirring. After stirring at room temperature for 1 hour, the mixture was filtered to obtain crystals. To the crystals, 300 ml of methyl ethyl ketone was added, stirred for 18 hours, filtered and dried under reduced pressure to obtain 7- [2- (2-aminothiazol-4-yl). 9.81 g) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] -3-1-pyridiniummethyl-3-cepem-4-carboxylate (yield: 95%) is obtained as an off-white solid.

Melting Point (° C): 170 to 172 (Decomposition)

IR (KRr): 1532, 1619, 1676, 1726, 1776cm ^-1

¹ H-NMR (DMSO-d ₆ ): ppm (δ) = 1.40 (s, 15H), 3.30 (m, 2H), 5.06 (d, 1H, J = 6.0Hz), 5.60 (m, 2H), 5.72 (m, 1H), 6.64 (s, 1H), 7.20 (broad s, 2H), 8.15 (m, 2H), 8.58 (m, 1H), 9.20 (d, 2H, J = 8.8 Hz), 9.48 (d , 1H, J = 6.0HZ)

(2) 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetamido] -3-1- 9.81 g (0.016 mole) of pyridiniummethyl-3-cepem-4-carboxylate is added to 9.8 ml of formic acid and stirred at room temperature for 30 minutes. The resulting solution is cooled to 10 ° C. and 4.9 ml of 55% hydroiodic acid is added dropwise and stirred at room temperature for 3 hours. 196 ml of methyl ethyl ketone was added to the reaction solution, the mixture was stirred for 1 hour, and the solvent was decanted. 196 ml of methyl ethyl ketone was further added to the solid in the flask, followed by stirring at room temperature for 18 hours. The resulting composition was filtered, washed with 33 ml of methyl ethyl ketone and dried under reduced pressure to obtain 13.1 g (yield: 98%) of crystalline ceftazidime bishydroiodide monohydrate as a pale yellow crystal.

Elemental Analysis (as C ₂₂ H ₂₂ N ₆ O ₇ S ₂ · 2Hl · H ₂ O)

Calculated (%): C; 32.21, H; 3.19, N; 10.24

Found (%): C; 32.40, H; 3.06, N; 10.11

Moisture (Karl Fisher): 2.30%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 1.

Example 5

(1) 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acet in 200 ml of anhydrous methylene chloride under nitrogen atmosphere Amido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 15g (0.025 mol) was suspended, 6.5 ml of hexamethyldisilazane (HMDS) and 1.3 ml of 1.0M trimethyliodosilane were added, followed by 12 hours. Heated to reflux. After the reaction solution was cooled to room temperature, 5.2 ml (0.064 mol) of pyridine and 51 ml of 1.0 M trimethyliodoran were added and heated to reflux for 3 hours. After cooling to room temperature, the insoluble material was filtered off and crystallized by adding 10 ml of ethanol to the solution. After removing the solvent, 300 ml of methyl ethyl ketone was added to the residue and stirred for 12 hours. The resulting solid was filtered, washed with 50 ml of methyl ethyl ketone and dried under reduced pressure to give 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop 14.4 g of p-2-oxyimino) acetamido] -3-methyl-1-pyridinium-3-cepem-4-carboxylate (yield: 93%) are obtained as an off-white solid.

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 1.

(2) 7- [2- (2-aminothiazol-4-yl) -2-syn- (2-t-butoxycarbonylprop-2-oxyimino) acetami obtained from (1) above 14.4 g of 3-acetoxymethyl-3-cepem-4-carboxylate is dissolved in 21.6 ml of formic acid and 10.8 ml of 55% hydroiodic acid and then stirred at 30 ° C. for 3 hours.

720 ml of methyl ethyl ketone was added to the solution to crystallize and stirred at room temperature for 1 hour. After passing through the solution carefully, 576 ml of methyl ethyl ketone was added to the obtained crystals and stirred for 18 hours at room temperature. The defect was filtered, washed with 100 ml of methyl ethyl ketone and dried under reduced pressure to yield 19.03 g (yield: 97%) of crystalline ceftazidime bishydroiodide monohydrate as a pale yellow crystal.

Elemental Analysis (as C ₂₂ H ₂₂ N ₆ O ₇ S ₂ · 2Hl · H ₂ O)

Calculated (%): C; 32.21, H; 3.19, N; 10.24

Found (%): C; 32.38, H; 3.40, N; 10.06

Moisture (Karl Fisher): 2.45%

Melting point, 1R and ¹ H-NMR data are the same as in Example 1.

Example 6

50 g of ceftazidime bishydroiodide monohydrate is dissolved in 150 ml of purified water, and 80 ml of 40% tetra n-butylammonium hydroside aqueous solution is added dropwise to the resulting solution at 10 to 15 ° C. for 30 minutes.

The reaction mixture is cooled to 0-5 [deg.] C. and stirred for 5 hours, then left at the same temperature for 12 hours. The resulting crystals were filtered, washed with 20 ml of purified water, washed twice with 200 ml of acetone, and then dried at room temperature for 3 hours. Then, 36.06 g of ceftazidime pentahydrate (yield: 93%) as a white crystal was converted into white crystals. To obtain.

Melting Point (° C): 216 to 224 (Decomposition)

IR (KRr): 1622, 1769cm ^-1

Purity (HPLC): 98.5%

¹ H-NMR (D ₂ O): ppm (δ) = 1.55 (s, 6H), 3.10, 3.63 (dd, 2H, J = 17.0Hz), 5.232 (d, 1H, J = 5.0Hz), 5.30, 5.60 (dd, 2H, J = 14.0Hz), 5.82 (d, 1H, J = 5.0Hz), 6.85 (s, 1H), 8.10 (m, 2H), 8.55 (m, 1H), 8.95 (d, 2H , J = 6.0 Hz)

Example 7

10 g of ceftazidime bishydroiodide monohydrate is dissolved in a mixed solvent of 20 ml of purified water and 20 ml, and 15 ml of 40% tetra n-butylammonium hydroside aqueous solution is added dropwise to the resulting solution at 10 to 15 ° C. for 30 minutes. 5 ml of purified water and 15 ml of acetone were continuously added to the reaction solution, a small amount of seed was added, and the temperature of the reaction solution was cooled to 0 to 5 ° C. and stirred for 5 hours. After standing at the same temperature for 12 hours, the mixture was filtered, washed with 4 ml of purified water, washed twice with 40 ml of acetone continuously, and dried under reduced pressure at room temperature for 3 hours to obtain 7.13 g of ceftazidime pentahydrate (yield). : 92%) is obtained as white crystals.

Purity (HPLC): 98.3%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 6.

Example 8

10 g of ceftazidime bishydroiodide monohydrate is added to a mixed solvent of 20 ml of purified water and 20 ml, and 10 ml of 40% tetra n-butylammonium hydroxide aqueous solution is added dropwise to the resulting solution at 10-15 占 폚. 5 ml of purified water and ethanol 101 were continuously added to the reaction solution, and 6 ml of 40% tetra n-butylammonium hydroside aqueous solution was added dropwise at 10 to 15 ° C over a portion thereof. A small amount of seed is added to the reaction solution, which is then adjusted to 0 to 5 ° C, stirred for 6 hours to crystallize and left at the same temperature for 12 hours. The resulting crystals were filtered, washed with 4 ml of purified water, washed twice with 30 ml of acetone continuously, and dried under reduced pressure at room temperature for 3 hours to yield 7.21 g of the target compound ceftazidime pentahydrate (yield: 93%). Obtained by crystals.

Purity (HPLC): 98.3%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 6.

Example 9

10 kg of ceftazidime bishydroiodide monohydrate was added to a mixed solvent of 20 L of purified water, 10 L of acetone and 10 L of ethanol, and 15.5 L of 40% tetra n-butylammonium hydroside aqueous solution was added to the resulting solution at 10 to 15 ° C. for 1 hour. Drop over. 5 L of purified water and 10 L of acetone- (1: 1) mixed solution were added to the reaction solution, the solution was added to a reactor in a sterile chamber through a sterile filter, and the temperature of the reaction solution was adjusted to 0 to 5 ° C., followed by stirring at the same temperature for 6 hours. And leave for 12 hours. The resulting crystals were filtered and washed sequentially with 4 L of purified water, 30 L of ethanol and 30 L of acetone, and then dried under reduced pressure at 25 to 30 ° C. for 10 hours to yield 7.37 kg of a ceftazidime pentahydrate (yield: 95%) as a target. Obtained by crystals.

Purity (HPLC): 98.5%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 6.

Example 10

50 g of ceftazidime bishydroiodide monohydrate is dissolved in 150 ml of purified water, and 68 ml of 2N NaOH aqueous solution is added to the resulting solution over 30 minutes. When the clear solution is cooled to 0 to 5 ℃ and stirred for 6 hours and left for 12 hours at the same temperature. The resulting crystals were filtered, washed with 50 ml of purified water, and then washed twice with 100 ml of acetone, followed by vacuum drying at room temperature for 2 hours to obtain 34.9 g (yield: 90%) of ceftazidime pentahydrate in white crystals.

Purity (HPLC): 98.0%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 6.

Example 11

The reaction was carried out in the same manner as in Example 10, except that 55 ml of 4% NH ₄ OH solution was used instead of 68 ml of 2N NaOH aqueous solution to obtain 34.95 g of a white crystals ceftazidime pentahydrate (yield: 90%). do.

Purity (HPLC): 98.1%

Melting point, 1R and ¹ H-NMR data of the product are the same as in Example 6.

Claims (9)

The 3-acetoxymethyl cephalosporin compound of formula (II) is then reacted with pyridine of formula (IV) in the presence of a compound of formula (III) to form crystalline ceftadidim bishydroiodide of formula (I '). A process for preparing ceftazidime pentahydrate of formula (I), characterized by obtaining a monohydrate and acting a base on the resulting intermediate compound (I '). In the above formula, R ₁ , R ₂ and R ₃ are each independently an alkyl group having 1 to 4 carbon atoms. A process according to claim 1, wherein the compound of formula (III) is trimethyliodinesilane ((CH ₃ ) ₃ Si-I). A process according to claim 1, characterized in that tetra n-butylammonium hydroxide of the following formula (V) is used as the phase transition base. A process according to claim 1, characterized in that 1 to 8 equivalents of compound of formula (III) and 1 to 8 equivalents of pyridine of formula (IV) are used for 1 equivalent of compound of formula (II). 2. Process according to claim 1, characterized in that the compound of formula (III) is used in admixture with an additional silylating agent. 6. The method of claim 5 wherein the silylating agent is selected from bistrimethylsilylacetamide, bistrimethylsilyltrifluoroacetamide, hexamethyldisilazane and bistrimethylsilylurea. A process according to claim 5, characterized in that 1 to 6 equivalents of silylating agent is used for 1 equivalent of the compound of formula II. The method according to claim 1, wherein 1 equivalent to 10 equivalents of base is used per equivalent of Compound (II). 9. A process according to claim 8, wherein 2 to 3 equivalents of base are used.