JPH01294667A - Thiazole derivative - Google Patents

Abstract

NEW MATERIAL:2-(2-Trimethylaminothiazol-4-yl)-2-methoxyiminoacetic acid lithium salt and its hydrate. USE:A synthetic intermediate for producing a cephalosporin antibiotic substance such as 7beta-[2-(2-amonothiazol-4-yl)-2-methoxyiminoacetamido]-3-[4-oxazol-5- yl-1- pyridinio]methyl-3-cephem-4-carboxylate. PREPARATION:The objective 2-(2-trimethylaminothiazol-4-yl)-2- methoxyiminoacetic acid lithium salt and its hydrate can be produced by hydrolyzing a lower alkyl ester of 2-(2-trimethylaminothiazol-4-yl)-2- methoxyiminoacetic acid in the presence of lithium hydroxide.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides cephalosporin antibiotics 1, such as 7β
-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide] -Produces -3-[4-oxazol-5-yl-1-pyridiniocomethyl-3-cephem-4-carboxylate This is among the new synthetic intermediates.

The above compound not only has a broad antibacterial spectrum in both gram-negative and gram-positive categories, but also has a broad antibacterial spectrum as described in JP-A-61-7280. It also shows strong activity against im bacteria,
It has been disclosed that it is very promising as an antibiotic.

<Prior Art> In the field of cef-10-sporin antibiotics, manufacturing costs are high due to the complexity of their chemical structures, so new and effective manufacturing methods are constantly being sought. In particular, the selection of raw materials for production is an important issue from the viewpoint of economical and industrial production of the target antibiotic.

In this regard, JP-A-52-102.293 states:
As an intermediate for the production of cephalosporin compounds, 2-
(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (1') and its sodium salt are described, and the free form can be obtained by neutralizing the sodium salt with acid (it is produced by .

Therefore, compound (1) is economically advantageous as a manufacturing intermediate.
Using the sodium salt of one of the raw materials, the following compound (
Although attempts were made to react with 11), no satisfactory results were obtained in terms of purity and yield.

<Problems to be Solved by the Invention> In order to overcome the above-mentioned drawbacks, the present inventors have made extensive studies on the salts of compound (I), and have found that the lithium salt is more effective against cephalosporin antibiotics than the sodium salt, etc. 9 For example, when the compound (!K) is reacted with borofluoride or borohydrofluoride in the production of substances, it has very good reaction control and the purity of the obtained antibiotic is also much better. Based on this discovery, the present invention was completed.

<Structure 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 compound (1) in the presence of lithium hydroxide.

This reaction is carried out in a solvent containing water, and the solvent is
Examples include alcohols such as methanol, ethanol, and isopropyl alcohol, ethers such as dioxane and tetrahydrofuran, and all other solvents that do not adversely affect the reaction. Although the amount of the solvent used is not particularly limited, it is preferably 4 parts or more per 1 part of the lower alkyl ester of metal compound (1).

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

Although the reaction temperature is not particularly limited, it is usually carried out under heating. After the reaction, the desired product can be obtained in high yield and purity by filtering the precipitate at room temperature or under cooling.

<Effects of the Invention> The target substance of the present invention may be purified if necessary, but instead of being purified, it can be treated with Vilsmeier reagent to form an active substance, and then condensed with the compound (!■). By subsequently removing the protecting group, the final cephaloborin derivative can be obtained in good yield. Incidentally, the above-mentioned active substance can also be isolated by filtration.
When the active form of t, and compound (II) are reacted under the same condensation and deprotection conditions as above, the final cephaloborin derivative can be obtained with good yield and purity (yield: 86-8
9 zero.

Purity 76-87 zero).

On the other hand, the sodium salt produces many by-products in the activation reaction with the Vilsmeier reagent under the same conditions as above.
It was difficult to isolate the active form, and when the final cephaloborin derivative was obtained through the subsequent condensation and deprotection reaction with compound (II), sufficiently good results were not obtained (
(yield: 760, purity: 72%), but there were difficulties in purifying the final material.

In general, cephalosporin antibiotics have poor stability1
Since it is easy to decompose, it is of great industrial value to obtain even a slightly higher yield and purity of the cardinal. Therefore, the fact that the above-mentioned improvement in yield and purity was observed when a lithium salt was used instead of a sodium salt can be said to be an extremely important result in terms of industrial production and economic efficiency of antibiotics.

The present invention will be explained below with reference to Examples and Reference Examples.

[Example 1] 2-(2-tritylaminothiazol-4-yl-2
-Methoxyimino acid lithium salt, syn form'
2-(2-tritylaminothiazol-4-yl)
100 o+1 isopropyl alcohol was added to 23.0 g of -2-methoxyiminoacetic acid methyl ester, stirred, and dissolved by heating. To this solution was added an aqueous solution of 2.52 g of lithium hydroxide monohydrate dissolved in 10 ml of water. After stirring at reflux temperature for 2.5 hours, one reaction solution was cooled,
The precipitate was collected by filtration. The filtrate was washed with isopropyl alcohol and dried under vacuum to obtain the title compound in a yield of 920 (purity 96k).

Quantification was performed using high performance liquid chromatography.

It was conducted under the following conditions.

Column: YMCpacked column A-3
12 (ODS) 6.0φX 150mm Detection: UV 254nm lithium salt) FT-NMR (90MHz, DMSO-da, δ, pp
m): 3.64 (3H, s, methoxy group) 6.57 (IH, s, H at 5-position of thiazole ring) 7.32
(15H,s, )-H of lythyl group) 8.89 (1
)1. S, H) Elemental analysis of the amino group at the 2-position of the thiazole ring C25H2°N, 0. Theoretical value C64,86, H4,6B, H9,0M analysis value C64,89, H4,95, H9,)3 obtained 2-
Crystals of lithium salt of (2-tritylaminothiazol-4-yl)-2-methoxyiminoacetate were analyzed by powder X-ray diffraction using copper X-rays with λ = 1.5418A using a nickel filter [d-lattice spacing] shows the following characteristics.

Unie”--l Yu17.74 VS 5.29 w13.
93 S 4.51
s7.63 5 4.47 m7.27
S 4.35 Stomach 8.92 m 4.25
s6.37 ta 3.96 s
5.95 s 3.72 冑However, in the table, S stands for "strong J", m stands for "moderate J", and W stands for "weak".
And V means "very".

[Example 2] 2-(2-tritylaminothiazol-4-yl)-2
-50 to 11.5 g of methoxyiminoacetic acid methyl ester
1 of methanol was added, stirred, and dissolved by heating. To this solution was added an aqueous solution of 1.26 g of lithium hydroxide monohydrate dissolved in 5 mJ2 of water. Stir at reflux temperature for 2.5 hours. The precipitated crystals were collected by filtration, washed with methanol, and dried under vacuum to obtain the title compound in a yield of 77% (purity: 97%).
k).

The IR and NMR spectra of the obtained compound are as shown in Example 1.
It was consistent with what was obtained.

[Reference Example 1] 13.8 ml of acetonitrile and 0 of dimethylacetamide
．． Cool 77ml of the mixture on ice, and add 0.77ml of phosphorus oxychloride.
Add 1 and stir for 30 minutes at the same temperature, then cool to -20°C,
-(2-tritylaminothiazol-4-yl)-2-
1.25 g of lithium methoxyiminoacetate was added and stirred at the same temperature for 30 minutes. Triethylamine 1.73n+1.
Then 7β-amino-3-[4-(oxazole-5-
yl)-1-pyridiniocomethyl-3-cephem-4-
1.70 g of carboxylic acid p-methoxybenzyl ester borofluoride borohydrofluoride was added. After stirring for 30 minutes under water cooling, one 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 for 2 hours under water cooling.

After the reaction, isopropyl ether 901 was added, and the precipitate was collected by filtration, washed with isopropyl ether, and dried under vacuum to obtain the title compound in a yield of 860 (purity 77!k).
, Quantification was performed using high performance liquid chromatography under the following conditions.

Column: YMCpacked column^-31
2 (ODS) 6.0φx 150m+a Detection: UV 254nm FT-NMR (90MHz, D, 0. δ, ppm)
:3.3B, 3.83(2H, ABq, J-1
8Hz, H at the 2nd position of the cephem ring) 4.06 (3H, s, methoxy group) 5.36 (IH, d, J-5) 1z, H at the 6th position of the cephem ring) 5.38.5.82 (2H , ^Bq, J=15Hz
, H of the CH2 group at the 3rd position of the cephem ring) 5.90 (IH, d, J = 5Hz, H of the CH2 group at the 7th position of the cephem ring)
) 7.13 (IH, s, H at position 5 of thiazole ring) 8.2
1 (1M, s, H at position 4 of oxazole ring) 8.56 (I
H, s, H at position 2 of oxazole ring) 8.34.8.98
(2H each, d each, J=7Hz, H of pyridine ring
) [Reference Example 2] -R-5-yl -1-pyridinio methyl-3-cephem-4-carboxylate trifluoro salt Acetonitrile 13.8g+1 and dimethylacetamide 0.7
7 ml of the mixed liquid was ice-cooled, 0.77 ml of phosphorous oxychloride was added, and after stirring at the same temperature for 30 minutes, it was cooled to -20°C. 2-
1.29 g of (2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid sodium salt was added and stirred at the same temperature for 30 minutes. Triethylamine 1.73ml1. Then, 1.70 g of 7β-amino-3-[4-(oxazol-5-yl)-1-pyridiniocomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride borohydrofluoride was added. Ta. After stirring for 30 minutes under water cooling, one 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 after cooling with water and stirring for 2 hours, 9On+1 of isopropyl ether was added.

After filtering the precipitate and washing with isopropyl ether,
The mu compound was obtained by vacuum drying in a yield of 760 (purity 7).
2 turtles).

The IR and NMR spectra of the obtained compound are shown in Reference Example 1.
It was consistent with what was obtained.

[Reference Example 3] A mixture of 27.6+al of acetonitrile and 1.54ml of dimethylacetamide was cooled on ice, and 1°54ml of phosphorus oxychloride was added.
m1 was added, stirred at the same temperature for 30 minutes, and then cooled to -20°C.
2-(2-tritylaminothiazol-4-yl)-
Add 2.50 g of 2-methoxyiminoacetic acid lithium salt,
The 6-reaction mixture was stirred at the same temperature for 30 minutes, collected by filtration, and dried under vacuum to obtain 2.03 g of the active substance. Take 1.40g of this.

Add 13.8a+1 acetonitrile and suspend at -20°C. Triethylamine 0.69ml1. Then 7β-amino-3-(4-(oxazol-5-yl)-1-pyridiniocomethyl-3-cephem-4-carboxylic acid p-
1.70 g of methoxybenzyl ester borofluoride borohydrofluoride was added. After stirring with water cooling for 30 minutes, it was poured into water, and the precipitate was collected by filtration. Add 30 ml of trifluoroacetic acid and 3 ml of anisole to the powder obtained by vacuum drying.
After cooling with water and stirring for 2 hours, isopropyl ether 9
After adding 0 ml of the precipitate, the precipitate was collected by filtration, washed with isopropyl ether, and then dried under vacuum to obtain the title compound in a yield of 89% (purity: 87k).

The IR and NMR spectra of the obtained compound are shown in Reference Example 1.
It was consistent with what was obtained.

[Reference Example 4] 13.8 ml of acetonitrile and 0 ml of dimethylformamide
．． Cool 64 ml of the mixture on ice, and add 0.77 ml of phosphorus oxychloride.
Add 1 and stir for 30 minutes at the same temperature, then cool to -20°C,
-(2-tritylaminothiazol-4-yl)-2-
1.25 g of lithium methoxyiminoacetate was added and stirred at the same temperature for 30 minutes. Triethylamine 1.731111
．． Then 7β-amino-3-[4-(oxazole-5
-yl)-1-pyridiniocomethyl-3-cephem-4
-Carboxylic acid p-methoxybenzyl ester borofluoride 1.70 g of borohydrofluoride was added. 30 with water cooling
After stirring for a minute, one reaction solution was poured onto wood, 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 cooled with water and stirred for 2 hours. After the reaction, 90 ml of isopropyl ether was added, and the precipitate was collected by filtration and washed with isopropyl ether.

Vacuum drying gave the title compound in a yield of 860 (purity 7).
6 zero).

The IR and NMR spectra of the obtained compound are shown in Reference Example 1.
It was consistent with what was obtained.

Claims (1)

[Claims] 2-(2-tritylaminothiazol-4-yl)-2
-Methoxyiminoacetic acid lithium salt and its hydrates