KR970004047B1 - Novel process for the preparation of cephem compound - Google Patents

Abstract

Synthetic method of cephalosporin antibiotics with high yield and high purity is disclosed in this invention. Cefpirome dihydroiodine or its hydrate is reacted with sulfuric acid in the pressure of oxidant such as m-chlorobenzoic acid, hydrogen peroxide, oxone, NaIO3, benzene iodine oxide, etc., in solvent such as water, organic solvent or mixture thereof at the temperature range of 0 to 5 degree Celsius.

Description

Novel Processes for Sepem Compound

The present invention relates to a novel method for preparing acid addition salts of cefem compounds represented by the following structural formula (I) and hydrates thereof useful as antibiotics.

The compound of formula (I) is a wide range of cephalosporin antibiotics with the common name "Cefpirome", which is classified as a so-called fourth generation cephaic antibiotic, and is clinically used in its sulfate form.

Several methods of making such sulfates are known in the prior art to date. Among these methods, for example, Korean Patent Publication No. 91-420 (January 25, 1991) discloses the reaction of betaine compound of the following formula (II), namely, cepirom itself with sulfuric acid, to react the sepirom of the formula (I). Processes for preparing sulfates are described.

However, since the betaine compound of formula (II) is difficult to be isolated by a conventional method, it can be isolated only by freeze-drying an aqueous solution that has passed through column chromatography or an anion exchange resin, and thus there are many problems in mass production. In addition, the yield was also a disadvantage.

In addition, Korean Patent Publication No. 91-4332 (June 26, 1991) and Korean Patent Publication No. 93-7816 (August 20, 1993) disclose sepiromiodic hydrochloride and its hydrate of formula (III) Processes for preparing the same are described.

Hydrogen iodide addition salt of the above formula (III) is known as an acid addition salt which is very suitable for isolating purely from an aqueous reaction solution because of its low solubility in water and excellent crystallinity.

Therefore, a number of attempts have been made to prepare clinically useful sepirom sulfate of structural formula (I) from such hydrosulfite iodide. Until now, however, in order to prepare the sepirom sulphate of formula (I) from the sepirom iodide hydrochloride of formula (III), in general, for example, in Korean Patent Publication No. 93-7816, Since the iodide hydrochloride compound must be neutralized with a base to be subjected to column chromatography or treated with an ion exchange resin to convert into a free betaine compound, which is a betaine of the formula (II), to be prepared by adding sulfuric acid to the sepiromide compound. Not only is the process complicated, but the problems in the separation of the intermediate sepirom as mentioned above remain intact, making it an efficient method for preparing the sepirom sulfate.

Therefore, the present inventors have long researched to find a method for preparing sepirom sulfate directly from sepirom hydroiodide without going through the sepirom, and isolated the betaine compound of formula (II) as an intermediate by using a specific oxidant. The present invention has been completed by finding a new method for preparing sepirom sulfate of formula (I) directly from the sepiromio iodide of formula (III).

Hereinafter, the present invention will be described in detail.

That is, the present invention relates to a process for preparing sepirom sulphate of formula (I) or its hydrate in high yield and high purity by reacting sepirom iodide hydrochloride of formula (III) or its hydrate with a specific oxidizing agent and sulfuric acid .

The process according to the invention is represented by the following scheme.

According to the method of the present invention as described above, since hydroiodic acid (HI) having a high affinity for cepirom is oxidized to iodine (I ₂ ) using an oxidizing agent and removed, sulfuric acid is added to produce sulfate. ) Is not required to separate betaine (ie, sepirom) or use an ion exchange resin.

As the specific oxidizing agent that can be used in the method of the present invention, both organic and inorganic oxidizing agents can be used, specifically m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, perbenzoic acid, sodium periodate (NaIO ₃ ), Oxone, iodosobenzene (PhIO), iodooxybenzene (PhIO ₂ ), and the like can be used. Among these oxidants, sodium periodate and iodoxybenzene are particularly preferably used in terms of reaction yield.

The reaction can preferably be carried out in a reaction inert solvent such as water, an organic solvent or a mixture of water and an organic solvent. The organic solvent may be an organic solvent such as alcohol such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane, chloroform and the like.

The reaction is carried out at a temperature of 0 to 50 ° C., particularly preferably at a temperature of 0 to 25 ° C.

The oxidizing agent is used at a ratio of 0.5 to 2 equivalents, preferably 1 equivalent to 1 equivalent of the starting compound (III) in carrying out the reaction according to the present invention.

The reaction is usually complete within 1 to 5 hours, preferably 1 to 3 hours. After the reaction is completed, the reaction compound may be worked up by a conventional method, for example, by distilling and concentrating the reaction solution followed by crystallization by adding an organic solvent to obtain the desired compound of the epiphysically sulfate compound (I). have. Preferred organic solvents used for crystallization of the compound of formula (I) include, for example, methanol, ethanol, isopropanol, acetone or mixed solvents thereof.

According to the present invention as described above, the free sepiromide compound of formula (II), which is difficult to be separated from the reaction mixture, is difficult to be separated directly from the sepirom hydroiodic acid salt of the formula (III) without the need to separate it as an intermediate. The desired clinically useful sepirom sulfate of formula (I) can be obtained in high yield and high purity.

The invention is illustrated in more detail by the examples described below, although the invention is not limited in any way by these examples.

Preparation Example 1

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3- (2,3-cyclopenteno-1-pyridinium) methyl] -sef Preparation of 3-M-4-carboxylate Dihydroiodide Monohydrate

Method A

2.7 ml (0.014 mol) of trimethylsilyl-trifluoromethanesulfonate was added dropwise to 20 ml of methylene chloride cooled to 5 ° C. 1.8 ml (0.015 mol) of 2,3-cyclopentenopyridine was added dropwise while maintaining the temperature of the resulting solution at 10 to 15 ° C, followed by 7- [2- (2-aminothiazol-4-yl 0.91 g (0.002 mol) of) -2-cin-methoxyiminoacetamido] cephalosporanic acid were added. The reaction mixture was refluxed under heating for 2 hours and then cooled to 5 ° C., and a solution of 2 g of potassium iodide dissolved in 4 ml of 2N hydrochloric acid was added dropwise to the reaction solution, followed by stirring for 2 hours. The resulting crystals were filtered off, washed with ice water and dried to give 1.54 g (97.6%) of the title compound as the desired white crystals.

IR (KBr, cm- ¹ ): 1785 (β-lactamcarbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.10-2.40 (m, 2H, cyclopentene-2H), 3.00-3.50 (m, 6H, cyclopentene-4H and -SCH _2- ), 3.90 (s, 3H, -OCH ₃ ), 5.20 to 5.80 (m, 4H, -CH ₂ -and lactam-2H), 6.70 (s, 1H, thiazole-H), 7.90 to 8.60 (m, 3H, pyridine ring -H).

Method B

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- 25.7 g (0.05 mol) of cef-3-em-4-carboxylate was dissolved in 120 ml of water, and 110 ml of 1N-HI and 240 ml of isopropyl alcohol were added dropwise to the resulting solution at 5 ° C. The solution was stirred for 1 hour, and the resulting crystals were filtered and dried to give 38.6 g (97.9%) of the title compound as white crystals.

The IR and ¹ H-NMR spectral data of the resulting compound are the same as in Method A.

Example 1

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate

After dissolving 1.65 g (7 mmol) of iodoxibenzene (PhIO ₂ ) in 150 ml of water, 7- [2- (2-aminothiazol-4-yl) -2- prepared in Preparation Example 1 was added to the resulting dispersion. Cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl] -cep-3-m-4-carboxylate dihydroiodide monohydrate ( Sepirom dihydroiodide monohydrate) 5.52 g (7 mmol) was slowly added at room temperature. The mixture was stirred at room temperature for 1 hour 30 minutes, then cooled to 0-5 ° C. and filtered to obtain a filtrate. The filtrate was extracted with ethyl ether (3 x 50 ml) and concentrated under reduced pressure until the volume of the aqueous layer was about 10 ml. The remaining solution was added 7.0 ml of 2N-H ₂ SO ₄ solution and 40 ml of ethanol and then stirred overnight under ice cooling. The resulting white crystals were filtered, washed sequentially with ethanol (3 × 10 ml) and acetone (3 × 10 ml) and dried to give 4.1 g (93%) of the title compound.

Purity (HPLC): 99.3%

IR (KBr, cm- ¹ ): 1785 (β-lactamcarbonyl)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.17 to 2.25 (m, 2H, cyclopentene-2H), 3.10 to 3.44 (m, 6H, cyclopentene-4H and -SCH _2- ), 3.88 (s, 3H, -OCH ₃ ), 5.15 to 5.86 (m, 4H, -CH ₂ -and lactam-2H), 6.71 (s, 1H, thiazole-H), 7.89 to 8.65 (m, 3H, pyridine ring -H).

Example 2

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate

0.79 g (1 mmol) of cepirom dihydroiodide monohydrate was dispersed in 10 ml of water, and 15 ml of methanol was added to the resulting dispersion to dissolve it. Under ice cooling, 0.24 g (1 mmol) of iodoxybenzene was added over 5 minutes and the mixture was stirred at 0-5 ° C. for 3 hours. The reaction mixture was filtered to give the filtrate, and then the methanol in the filtrate was distilled off under reduced pressure, and the aqueous layer was washed with ethyl ether (3 x 10 ml). The aqueous layer was distilled under reduced pressure and concentrated to about ₄ ml, to which 1 ml of 2N-H ₂ SO ₄ was added, followed by dropwise addition of 10 ml of ethanol. The reaction mixture was seeded with crystals of the desired product under ice-cooling, then stirred overnight and filtered. The product was washed with ethanol (3 × 2 ml) and ethyl ether (3 × 2 ml) and dried to give 0.54 (86%) of the title compound as white.

Purity (HPLC): 99.2%

The IR and ¹ H-NMR spectral data of the target compound produced are the same as in Example 1.

Example 3

7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate

6.5 g (0.4 equiv) of sodium periodate NaIO ₃ was dissolved in 12 ml of water at 0 ° C, and 6.0 ml of 1N-H ₂ SO ₄ was added. To this was added 5.0 g (6.3 mmol) of cepirom dihydroiodide monohydrate little by little, the reaction mixture was stirred at 0 ° C. for 30 min, filtered and washed with 10 ml of water. The filtrate was washed with ethyl ether (4 x 25 ml) and the aqueous layer was distilled off under reduced pressure and concentrated to a volume of about 8 ml. 40 ml of ethanol was added to the residue, stirred at 0 ° C. for 2 hours, and filtered. The filtered product was washed sequentially with ethanol (2 × 10 ml) and acetone (2 × 10 ml) and dried to give 3.3 g (83%) of the title compound as the off-white solid.

Purity (HPLC): 99.15%

The IR and ¹ H-NMR spectral data of the target compound produced are the same as in Example 1.

Example 4

Reaction was carried out in substantially the same manner as in Example 1, except that 2.2 g (7 mmol) of 55% m-chloroperbenzoic acid was used instead of iodoxibenzene as the oxidizing agent to obtain the desired sepirom sulfate monohydrate. (Yield: 80%). The IR and ¹ H-NMR spectral data of the target compound produced are the same as in Example 1.

Example 5

The reaction was carried out in substantially the same manner as in Example 1, except that 4.3 g (7 mmol) of oxone was used in place of iodoxibenzene as the oxidizing agent, to obtain the desired sepirom sulfate monohydrate (yield: 82%). ). The IR and ¹ H-NMR spectral data of the target compound produced are the same as in Example 1.

Example 6

Reaction was carried out in substantially the same manner as in Example 1, except that 1.66 g (7 mmol) of 32% by weight peracetic acid was used instead of iodoxibenzene as the oxidizing agent to obtain the desired sepirom sulfate monohydrate ( Yield 82%). The IR and ¹ H-NMR spectral data of the target compound produced are the same as in Example 1.

Claims (5)

A process for preparing the sepirom sulphate of formula (I) or a hydrate thereof, characterized by reacting cepirom dihydroiodide of formula (III) or a hydrate thereof with an oxidizing agent and sulfuric acid. The method of claim 1, wherein m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, perbenzoic acid, sodium periodate (NaIO ₃ ), oxone, iodosobenzene (PhIO) or iodooxybenzene (PhIO ₂₎ A process for preparing the sepirom sulfate of formula (I) or a hydrate thereof, characterized by the use of 3. The process according to claim 2, wherein sodium iodate or iodoxybenzene are used as the oxidizing agent, to prepare the sepirom sulfate of formula (I) or a hydrate thereof. 2. Process according to claim 1, characterized in that the reaction is carried out in a reaction inert solvent, to prepare the sepirom sulfate of formula (I) or a hydrate thereof. 5. Process according to claim 4, wherein the reaction inert solvent is water, alcohols, halogenated hydrocarbons or mixtures thereof.