JP2662414B2 - Thiazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to cephalosporin antibiotics, for example, 7β
-[2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4-oxazol-5-yl-1-pyridinio] methyl-3-cephem-
The present invention relates to a novel synthetic intermediate for producing 4-carboxylate.

The above compounds are described in JP-A-61-7280,
It is disclosed that it has a broad antibacterial spectrum in general for both Gram-positive bacteria and also has a strong activity against Pseudomonas aeruginosa, and is extremely demanded as an antibiotic.

<Prior Art> In the field of cephalosporin antibiotics, since the production cost is increased due to the complexity of the chemical structure, a new and effective production method is always sought. In particular, the selection of the raw material for production is an important problem from the viewpoint of economical and industrial production of the target antibiotic.

In this connection, JP-A-52-102,293 discloses 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid (I) and 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid as intermediates for producing cephalosporin-based compounds. The sodium salt is described, and the educt is produced by neutralizing the sodium salt with an acid.

Therefore, the economically advantageous compound (I) is used as a production intermediate.
Of 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-
Condensation reaction with cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride borofluoride (II) was attempted, but satisfactory results were not always obtained in terms of purity and yield.

<Problems to be Solved by the Invention> The present inventors have proposed a compound (I)
As a result of diligent studies on the salts of the compound, the lithium salt, when compared with the sodium salt, etc., has a very high reactivity when condensed with compound (II) in the production of cephalosporin antibiotics. The present inventors have also found that the purity of the obtained antibiotic is far superior, and completed the present invention.

<Constitution of the Invention> The compound of the present invention can be easily produced by the following method. That is, it is produced by hydrolyzing a lower alkyl ester of the compound (I) in the presence of lithium hydroxide.

This reaction is carried out in a solvent containing water. Examples of the solvent include alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as dioxane and tetrahydrofuran, and all other solvents which do not adversely affect the reaction. No. The amount of the solvent to be used is not particularly limited, but is preferably 4 sites per 1 part of the lower alkyl ester of the compound (I).

The lithium hydroxide used may be either an anhydride or a hydrate, and may be used as an aqueous solution. It is sufficient that the amount of the lithium hydroxide to be used is at least equimolar to the lower alkyl ester of the compound (I).

Although the reaction temperature is not particularly limited, it is usually performed under heating. Thus, after the reaction, the target substance can be obtained in high yield and high purity by collecting the precipitate by filtration at room temperature or under cooling.

<Effect of the Invention> The target substance of the present invention may be purified if necessary.
Without purification, after treatment with the Vilsmeier reagent to form the active form, condensation with compound (II), and subsequent removal of the protecting group, the final cephaloporin derivative can be obtained in good yield. . The above active form can be isolated by filtration. When the isolated active form and compound (II) are reacted under the same condensation and deprotection conditions as described above, good efficiency and good purity can be obtained. To obtain the final cephaloporin derivative (yield 86-89%, purity 76-
87%).

On the other hand, sodium salt has many by-products in the activation reaction with Vilsmeier reagent under the same conditions as above, and it is difficult to isolate its active form. When the final cephaloporin derivative was obtained by the condensation / deprotection reaction, satisfactory results were not obtained (76% yield, 72% purity), and purification of the final material was difficult.

In general, cephalosporin antibiotics have poor stability and are easily decomposed, so that obtaining a crude product with a high yield and purity even in a small amount is of great industrial value. Therefore,
When the lithium salt was used in place of the sodium salt, the improvement in yield and purity described above was recognized as a very important achievement in the industrial production and economy of antibiotics.

 Hereinafter, the present invention will be described with reference to Examples and Reference Examples.

[Example 1] 2- (2-tritylaminothiazol-4-yl) -2
-Lithium methoxyiminoacetate, syn isomer 2- (2-tritylaminothiazol-4-yl)-
100 ml of isopropyl alcohol was added to 23.0 g of 2-methoxyiminoacetic acid methyl ester, stirred, heated and dissolved. Lithium hydroxide / 1 dissolved in 10 ml of water was added to this solution.
An aqueous solution of 2.52 g of hydrate was added. After stirring at the reflux temperature for 2.5 hours, the reaction solution was cooled and the precipitate was collected by filtration. The filtrate was washed with isopropyl alcohol and dried in vacuo to give the title compound in 92% yield (purity 96%).

The quantification was performed using high performance liquid chromatography under the following conditions.

Column: YMC packed column A-312 (0DS) 6.0φ × 150mm Detection: UV254nm FT-NMR (90 MHz, DMSO-d ₆ , δ, ppm): 3.64 (3H, s, methoxy group) 6.57 (1H, s, H at the 5-position of the thiazole ring) 7.32 (15H, s, H at the trityl group) 8.69 (1H, s, H of the amino group at the 2-position of the thiazole ring) Elemental analysis C ₂₅ H ₂₀ N ₃ O ₃ SLi · 3 / 4H ₂ O Theoretical value C64.86, H4.68, N9.08 Analysis value C64.89, H4.95, N9.13 The resulting 2- (2-tritylaminothiazole-4-
Il) -2-methoxyiminoacetic acid lithium salt crystal shows the following characteristics by powder X-ray diffraction [d = lattice spacing] using λ = 1.5418 ° copper X-rays using nickel as a filter. d strength d strength 17.74 VS 5.29 w 8.93 S 4.51 s 7.63 S 4.47 m 7.27 S 4.35 w 6.92 m 4.25 s 6.37 m 3.96 s 5.95 s 3.72 w However, in the table, s is "strong", m is "moderate", w means "weak" and v means "very".

Example 2 2- (2-tritylaminothiazol-4-yl) -2
-Lithium methoxyiminoacetate, syn isomer 2- (2-tritylaminothiazol-4-yl)-
50 ml of methanol was added to 11.5 g of 2-methoxyiminoacetic acid methyl ester, stirred, heated and dissolved. To this solution was added an aqueous solution of 1.26 g of lithium hydroxide monohydrate dissolved in 5 ml of water. Stir at reflux temperature for 2.5 hours. The precipitated crystals were collected by filtration, washed with methanol, and dried in vacuo to give the title compound in 77% yield (purity 97%).

The IR and NMR spectra of the obtained compound were consistent with those obtained in Example 1.

Reference Example 1 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate trifluoroacetate 13.8 ml of acetonitrile and 0.77 ml of dimethylacetamide
The mixture was cooled on ice, and 0.77 ml of phosphorus oxychloride was added.
After stirring for 2 minutes, the mixture was cooled to -20 ° C, 1.25 g of lithium 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetate was added, and the mixture was stirred for 30 minutes at the same temperature. 1.73 ml of triethylamine, followed by 1.70 g of 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride borofluoride Was added. After stirring on ice for 30 minutes, the reaction solution was poured into water, and the precipitate was collected by filtration. 30 ml of trifluoroacetic acid and 3 ml of anisole were added to the powder obtained by vacuum drying, and the mixture was stirred on ice for 2 hours. After the reaction,
90 ml of isopropyl ether was added, and the precipitate was collected by filtration, washed with isopropyl ether, and dried in vacuo to give the title compound in 86% yield (purity 77%). The quantification was performed using high performance liquid chromatography under the following conditions.

Column: YMC packed column A-312 (0DS) 6.0φ × 150mm Detection: UV254nm FT-NMR (90 MHz, D ₂ O, δ, ppm): 3.38, 3.83 (2H, ABq, J = 18 Hz, H at the 2nd position of the cephem ring) 4.06 (3H, s, methoxy group) 5.36 (1H, d, J = 5 Hz, H at position 6 of the cephem ring) 5.38,5.82 (2H, ABq, J = 15 Hz, H of CH ₂ group at position 3 of the cephem ring) 5.90 (1H, d, J = 5 Hz, H at position 7 of the cephem ring) 7.13 (1H, s, H at the 5-position of the thiazole ring) 8.21 (1H, s, H at the 4-position of the oxazole ring) 8.56 (1H, s, H at the 2-position of the oxazole ring) 8.34,8.98 (2H each, d, J each = 7 Hz, H of pyridine ring) [Reference Example 2] 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4-oxazol-5-yl-1-pyridinio] methyl-3-cephem-4-carboxylate trifluoroacetate 13.8 ml of acetonitrile and 0.77 ml of dimethylacetamide
The mixture was cooled on ice, and 0.77 ml of phosphorus oxychloride was added.
After stirring for 30 minutes, the mixture was cooled to -20 ° C, 1.29 g of sodium 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetate was added, and the mixture was stirred for 30 minutes at the same temperature. 1.73 ml of triethylamine, then 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-
Cefem-4-carboxylic acid p-methoxybenzyl ester borofluoride 1.70 g was added. After stirring on ice for 30 minutes, the reaction solution was poured into water, and the precipitate was collected by filtration. 30 ml of trifluoroacetic acid is added to the powder obtained by vacuum drying.
And 3 ml of anisole were added, and the mixture was stirred on ice for 2 hours. After the reaction, 90 ml of isopropyl ether was added, and the precipitate was collected by filtration, washed with isopropyl ether, and dried in vacuo to give the title compound in 76% yield (purity 72%).

The obtained compound IR and NMR spectra were identical to those obtained in Reference Example 1.

[Reference Example 3] 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate trifluoroacetate 27.6 ml of acetonitrile and 1.54 ml of dimethylacetamide
The mixture was cooled on ice, and 1.54 ml of phosphorus oxychloride was added.
After stirring for 30 minutes, the mixture is cooled to -20 ° C, 2.50 g of lithium 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetate is added, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture was collected by filtration and dried under vacuum to obtain 2.03 g of the active substance. 1.4 of these
Take 0 g, add 13.8 ml of acetonitrile and suspend at -20 ° C. 0.69 ml of triethylamine, then 7β-amino-
3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride borohydrofluoride 1.
70 g were added. After stirring on ice for 30 minutes, the mixture was poured into water, and the precipitate was collected by filtration. 30 ml of trifluoroacetic acid and 3 ml of anisole were added to the powder obtained by vacuum drying, and the mixture was stirred on ice for 2 hours. After the reaction, 90 ml of isopropyl ether was added, and the precipitate was collected by filtration, washed with isopropyl ether, and dried in vacuo to give the title compound in 89% yield (purity 87%).

The obtained compound IR and NMR spectra were identical to those obtained in Reference Example 1.

Reference Example 4 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate trifluoroacetate 13.8 ml of acetonitrile and 0.64 ml of dimethylformamide
The mixture was cooled on ice, and 0.77 ml of phosphorus oxychloride was added.
After stirring for 2 minutes, the mixture was cooled to −20 ° C., 1.25 g of lithium 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetate was added, and the mixture was stirred for 30 minutes at the same temperature. 1.73 ml of triethylamine, followed by 1.70 g of 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride borofluoride Was added. Ice cold 3
After stirring for 0 minutes, the reaction solution was poured into water, and the precipitate was collected by filtration. 30 ml of trifluoroacetic acid and 3 ml of anisole were added to the powder obtained by vacuum drying, and the mixture was stirred on ice for 2 hours. After the reaction,
90 ml of isopropyl ether was added, and the precipitate was collected by filtration, washed with isopropyl ether, and dried in vacuo to give the title compound in 86% yield (purity 76%).

The IR and NMR spectra of the obtained compound were consistent with those obtained in Reference Example 1.

Claims (1)

(57) [Claims] (1) 2- (2-tritylaminothiazole-4)
-Yl) -2-Methoxyiminoacetic acid lithium salt and hydrate thereof