JPH0156072B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3-methylene cefamycin derivatives, more specifically,
This invention relates to a method for producing 3-methylene cefamycin derivatives using Raney nickel in the reaction solvent of No. 9.

Conventionally, a method for reducing a substituted mercaptomethyl group at the 3-position of a cephalosporin compound to convert it into a 3-exomethylene derivative is disclosed, for example, in JP-A-47-20188.

However, no example has been found regarding a cefamycin compound, which is 7-methoxycephalosporin. The only example listed is JP-A-Sho.
No. 49-41394, in which the substituent at the 3-position, which is the group to be reduced, is an acetoxy or carbamoyloxy group, and the reducing agent used is also limited to chemical reducing reagents.

In general, the reactivity of the substituted methyl group at the 3-position of cefamycin-based compounds that have a methoxy group at the 7-position is significantly inferior to that of non-methoxy cephalosporin-based compounds, so the reaction that proceeds with cephalosporin-based compounds is directly followed by cefamycin. It is not easy to infer whether or not it can be applied to other types of compounds.

The present invention has already been developed by the inventors in Japanese Patent Publication No. 53-41233.
3 isolated from the culture solution of the actinomycete Streptomyces chayatriusis SF-1623 disclosed in the issue.
A new cefamycin antibiotic having a sulfothiomethyl group at the following formula (1): In the formula, R represents hydrogen or a protecting group for an amino group.

The SF-1623 substance shown by or its N-protected form is used as a starting material, and this is reduced using Raney nickel in a solvent with a pH of 7 to 9 to obtain the following formula (2): In the formula, R has the same meaning as in formula (1).

The purpose of the present invention is to provide a novel method for producing a 3-methylene cefamycin derivative represented by the following formula.

3-Exomethylene compounds are important synthetic intermediates for various useful 3-substituted methyl ∧ ∨ derivatives, and several production methods are known. In the synthesis of the exomethylene form by reduction of , a 3-methyl form is produced as a by-product, which is a drawback of this method (RRChauvette et al., J.org.chem.
vol.38, pp2994, 1973).

The inventors took these points into consideration and developed SF-
Regarding the 1623 substance and its N-protected form, we investigated various reduction reactions using Raney nickel for the purpose of obtaining the 3-exomethylene form, and as a result, we succeeded in obtaining the target compound in good yield and completed the present invention. I reached it.

In the present invention, the compound of formula (1) is used as a starting material, but the N-protecting group of the compound of formula (1) must be resistant to reduction reactions, such as benzoyl group, Examples include p-nitrobenzoyl group, t-butoxycarbonyl group, and acetyl group.

These protecting groups are not essential for carrying out the reduction reaction of the present invention, but are introduced to facilitate the purification of the 3-exomethylene compound obtained after the reaction.

Furthermore, since the obtained N-protecting group-3-exomethylene compound can be dissolved in an organic solvent, it has the advantage that it can be easily separated from unreacted substances and other impurities.

The 3-sulfothiomethyl group of the compound of formula (1) is
When treated with chemical reducing agents such as zinc, it produces thiolactone. The reduction reaction in the present invention is carried out in a hydrogen atmosphere in the presence of Raney nickel.

As a reaction solvent, water or methanol, ethanol, dioxane, tetrahydrofuran, N,N-
An organic solvent such as dimethylformamide, a mixed solvent thereof, or a water-containing solvent thereof is used.

In the reaction of the present invention, the hydrogen pressure is 1 to 5 atm, the reaction temperature is 10 to 60°C, and the reaction time is generally 2 to 10 hours, although it varies depending on the reaction temperature.

In the present invention, the pH of the reaction solution is set within the range of 7 to 9. When the reduction reaction is carried out in a reaction solution with a pH of 9.5 or higher under the above conditions, in addition to the target compound, the exomethylene form of formula (2), the by-product of the 3-methyl form cannot be ignored, and the production ratio is may exceed 30%. Raneynickel does not work effectively on the acidic side. When the reaction solution has a pH in the range of 7 to 9, the by-formation of the 3-methyl compound is suppressed to a minimum, and its production ratio is 5% or less.

Therefore, when using Raney nickel, it is important to thoroughly wash it with water to remove excess alkali before use.

The reaction product can be easily purified by synthetic adsorption resin, column chromatography using Diaion HP-20, Cephadex LH-20, or the like, or organic solvent extraction using ethyl acetate or the like.

The present invention will be explained in more detail below based on examples.

[Example 1] 7β-(D-5-amino-5-carboxyvaleramide)-7α-methoxy-3-sulfothiomethyl-3-cephem-4-carboxylic acid (SF-
14g of sodium salt of 1623 substance) was dissolved in a mixed solvent of 100ml of water and 50ml of dioxane, adjusted to pH 8.5 with caustic soda, and stirred at a temperature of 10 to 20°C.
Dioxane solution of 11g of butoxycarboxylic anhydride
50ml was added dropwise over 2 hours. During this time, the pH of the reaction solution was maintained at 8 to 9. After further stirring at room temperature for 4 hours, the pH of the reaction solution was adjusted to 6.5 and concentrated to about 80 ml. The resulting concentrated solution was washed with 100 ml of ethyl acetate, and the aqueous layer was further concentrated to 50 ml under reduced pressure, then applied to a Diaion HP-20 column (IL), developed with water, and fractionated in 15 ml portions ( fraction) was collected. Fractions No. 80 to 125 were collected and concentrated under reduced pressure, then freeze-dried to obtain 7β-
(D-5-t-butoxycarbonylamino-5-
carboxyvaleramide)-7α-methoxy-3
12.5 g of sodium salt of -sulfothiomethyl-3-cephem-4-carboxylic acid was obtained. Then this
2.0 g was dissolved in 100 ml of 50% ethanol aqueous solution, and 10 g of Raney nickel thoroughly washed with distilled water was added thereto. The reaction solution had a pH of 8.7.

After hydrogenation for 5 hours at room temperature in a hydrogen gas atmosphere, the resulting reaction solution was filtered and the catalyst was washed with 100 ml of water. Combine the liquid and catalyst washing liquid and add
After adjusting the pH of the whole to 6 by adding 1N hydrochloric acid, ethanol was distilled off. Then, after adjusting the pH to 2 with 1N hydrochloric acid,
Extracted with 200ml of ethyl acetate.

After drying the extract with anhydrous magnesium sulfate,
When concentrated to dryness, 1.3 g of pale yellow powder was obtained.
This product was dissolved in 5 ml of ethyl acetate, applied to a column packed with 500 ml of Sephadex LH-20, developed with a mixed solvent of ethyl acetate and methanol (25:3), and fractions of 15 ml each were collected. Collect fractions No. 32 to 44 and concentrate to dryness.
1.1 g of white powder of 7β-(D-5-t-butoxycarbonylamino-5-carboxyvaleramide)-7α-methoxy-3-methylene-3-cephem-4-carboxylic acid was obtained.

Silica gel thin layer chromatography (n-butanol:acetic acid:water:butyl acetate=2:1:1:
1): Rf=0.60 [Example 2] 7β-(D-5-benzoylamino-5-carboxyvaleramide)-7α-methoxy-3-sulfothiomethyl-3-cephem-4-carboxylic acid sodium salt 1.0 g was dissolved in 70 ml of water, 6 g of Raney nickel thoroughly washed with water was added, and hydrogenation was carried out at room temperature in a hydrogen gas atmosphere of 2 atm for 4 hours.

After filtering the reaction solution and washing with 50 ml of water, the solution and washing solution were combined in the same manner as in Example 1, and the pH was adjusted with 1N hydrochloric acid.
2 and extracted with 150 ml of ethyl acetate. The extract was dehydrated with anhydrous magnesium sulfate and then concentrated to dryness to obtain 0.6 g of pale yellow powder. Dissolve this in 2 ml of methanol and use Sephadex LH-20.
The mixture was applied to a 200 ml column and developed with methanol, and 7 ml fractions were collected. Fraction No.28
~37 was collected and concentrated to dryness to obtain 7β-(D-5-benzoylamino-5-carboxyvaleramide)-
7α-methoxy-3-methylene-3-cephem-
0.45 g of white powder of 4-carboxylic acid was obtained.

Silica gel thin layer chromatography (n-butanol:acetic acid:water=2:1:1): Rf=0.65.

Claims (1)

[Claims] 1 Formula: In the formula, R represents hydrogen or a protecting group for an amino group. SF-1623 substance shown in or its N-protected form
Characterized by reduction using Raney nickel in a reaction solvent with a pH of 7 to 9. Formula: In the formula, R has the same meaning as above. A method for producing a 3-methylene cefamycin derivative shown in