JPS6043073B2 - Method for producing cephalosporin compounds using new silylating agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention involves silylating 7-aminodesacetoxycephalosporanic acid represented by the general formula (1) to produce a silyl ester of the acid as represented by the general formula (■). ■) [However, R1
and R2 is a lower alkyl group], the compound is acylated, and then desilylated to produce a cephalosporin compound represented by the general formula (■). The present invention relates to an improved method for producing the cephalosporin compound, characterized in that a novel compound represented by the general formula (■), N,N-dimethyl-trimethylsilylforminium chloride, is used as a curing agent.

There are various known methods for producing cephalosporin antibiotics, and some representative examples include 7-aminodesacetoxycephalosporanic acid or 7-aminocephalosporanic acid. There is a method of silylation using hexamethyldisilazane or a method of silylation using bis-trimethylsilylurea or bis-trimethylsilylacetamide, and these methods have been widely used. However, all of these methods require the use of expensive silylating agents, and the reflux operation is performed under high temperature conditions using a high-boiling point solvent, resulting in the decomposition of 7-aminodesacetoxycephalosporanic acid. However, there are also disadvantages such as the need for extra operations to replace the reaction solvent after the reaction, resulting in an increase in the cost of the product.

Apart from the above method, there is also a method of silylation using trimethylchlorosilane as a silylating agent, but this method requires the use of an organic base such as triethylamine and requires even more severe reaction conditions. However, since the silylation rate is not as reactive as expected, it cannot be said that there is any advantage.

In the present invention, in order to overcome all the difficulties found in the above-mentioned conventionally known methods and to provide a new, advanced and improved technical method, a new silylating agent of the general formula (V
) is intended to utilize N,N-dimethyl-trimethylsilylformamidinium chloride.

Using this novel silylating agent of the present invention, 7-
Aminodesacetoxyseporanic acid and 7-aminocephalosporanic acid can be silylated. For now reference, the known techniques for the production of cephalosporin compounds are described in U.S. Pat. No. 3,985,741
- After dissolving aminodesacetoxycephalosporanic acid in water and acetone solvent with triethylamine,
D-N-(2-methoxycarbonyl-1-methylvinyl)-α. A cephalosporin compound is obtained in low yield by reaction with sodium amino-α-(4-hydroxyphenyl)acetate.

British Patent No. 1240687 discloses that after dissolving 7-aminodesacetoxycephalosporanic acid in an aqueous sodium carbonate solution, the resulting sodium salt is D-(-)-α
The corresponding cephalosporin compound is obtained by acylating the 2,6-lutidine salt of -(p-hydroxyphenyl)-α-(t-butoxycarbonylamino)acetic acid with an acid anhydride obtained by reacting with an alkyl haloformate. Manufactured. However, this method has disadvantageous manufacturing conditions due to the complicated acylation step, resulting in a low yield. Further, in U.S. Pat. No. 4,160,863, 7-aminodesacetoxycephalosporanic acid is silylated using hexamethyldisilazane and reacted with D-p-hydroxyphenylglycyl chloride hydrochloride hemidioxane to produce a cephalosporin compound. is reported.

In all of these techniques, 7-aminodesacetoxycephalosporanic acid is converted to the following general formula (■) [where R'' is an alkali metal Na, K or R3NH2
(However, R3 is a lower alkyl group) or -Si(
CH3)3], protect the carboxyl group as an inorganic salt, or combine it with an organic amine to form an organic amine salt, or use the silylating agents hexamethyldisilazane, bis-trimethylsilylacetamide, bis-
After protecting the carboxyl group by silylation by reaction with trimethylsilyl urea or trimethylchlorosilane in the presence of an organic amine, the general formula (■) and the general formula (■) [However, R4 is an alkali metal Na or K] Yes, R5
is a methyl or ethyl group] to produce the corresponding cephalosporin compound.

In the present invention, 7-aminodesacetoxycephalosporanic acid is converted to 20 to 50
Since it can be easily silylated by reacting in a polar solvent at ℃, the silylated product shown above as the general formula (■) obtained in this way can be combined with the acid anhydride also shown above as the general formula (■). By reacting to acylate, then hydrolyzing to remove the protecting groups of the silyl and amino groups, and further purifying the resulting crude product in an organic solvent, the general formula (■
) can be obtained in high yield and purity.

Next, Examples will be shown to explain the method of the present invention in more detail.

Example 1 36.5 grams (0.
2 mol) of N,N-dimethyl-trimethylsilylformamidinium chloride was dissolved in a solution containing 20 grams (A). 093 mol) of 7-aminodesacetoxycephalosporanic acid was added, the temperature was gradually raised, and stirring was continued while maintaining a maximum of 50°C. As a result, silylation progressed and the solution became clear.

While the above solution was cooled to 0°C, it was placed in a separate reaction vessel for 5 min.
0ml of acetonitrile and 100w1.1(7)N,N
- Add dimethylformacide and add 10ml (7)
N,. After adding N-dimethylbenzylamine and cooling to −30° C., 13 ml of ethyl chloroformate are added.

Following this, 35 grams of DN-(2-ethoxycarbonyl-1-methylvinyl)-α-amino-α-(4-hydroxyphenyl)-acetic acid was immediately added and allowed to react. After stirring the three powders at the same temperature, the cooled silylated 7-aminodesacetoxycephalosporanic acid solution was added over 1 hour while maintaining the low temperature of -30°C, and then pyridine was added. Gradually add to adjust the pH to 5-6.

After reacting for another 2 hours at the same temperature and adding water, a clear solution was obtained. After stirring for another 1 hour, 300 ml of acetonitrile was added and the mixture was stirred overnight. filtering the precipitated product;
Washing with acetonitrile, dispersing in 65% acetonitrile aqueous solution, stirring at 20-30°C, filtering and drying yields the target compound 7-[D-α-amino-2-(4-
25 grams of hydroxyphenyl)acetamide]-desacetoxycephalosporanic acid are obtained. This product is used for thin layer chromatography (Rf=0.28, silica gel 60
coating plate) and chemical analysis (content 930rr1cg/Mg
, moisture 4.5%, acidity 4.8. Specific optical rotation 1161r (1
%, H2O), acid content 99.

4%, base content 99.6%), it was confirmed to be the target compound.

Example 2 By the same operation as in Example 1, 32 grams of D-N-(
2-methoxycarbonyl-1-methylvinyl)-α-
24 grams of the desired compound were obtained using sodium amino-α-(4-hydroxyphenyl)acetate.

The analysis results were the same as in Example 1. Example 3 In a 500 ml container, 35 grams of D-N-(2-ethoxycarbonyl-1-methylvinyl)-α-amino-α-
Take sodium (4-hydroxyphenyl)acetate and
Add 50 ml of N,N-dimethylacetamide and slowly cool to -10°C. While maintaining this temperature, add 100 ml (7) of N,N-dimethylbenzylamine and 19 grams of t-butoxycarbonyl. Add chloride and react for 1.5 hours at the same temperature.

Separately, put 20 grams of 7-aminodesacetoxycephalosporanic acid in another 500 mL container, and add 100 ml (
: Add N,N-dimethylacetamide and 37 grams of N,N-dimethyl-trisilylformamidinium chloride, which is the new silylating agent of the present invention, and gradually warm the mixture.
Dissolve at a temperature below 0°C.

After cooling, it is appropriately added to the cooled solution of the mixed acid anhydride obtained by the reaction, and stirring is continued at -10°C for 2 hours. During this time, the pH of the reaction solution is adjusted to 6-7 using a suitable organic amine (pyridine, triethylamine, diethylamine, lutidine, picoline, etc.). After adjusting the reaction, 100 mL of water was added and stirring was continued overnight to precipitate the target compound as a crude crystalline product.

When this is filtered, washed with acetonitrile, and dried, the
grams of product are obtained. The content of the target compound in this product was 80%.

Example 4 100 mt of the crude product crystals obtained in Example 3
of water and 200 ml of acetonitrile,
Warming the temperature to 30-40°C and gradually adding diluted hydrochloric acid will result in a clear solution.

Claims (1)

[Claims] 1 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 7-aminodesacetoxycearosporanic acid represented by (I) is silylated to form general formula (II): ▲Math. , chemical formulas, tables, etc. ▼ After forming a silyl ester of the acid such as (II), the general formula (III):
▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [However, R
_1 and R_2 are lower alkyl groups] By reacting with a mixed acid anhydride represented by acylation of the compound and then desilylating it, the general formula (IV): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( In the method for producing the cephalosporin compound represented by IV), the silylating agent is a novel compound represented by the general formula (V): An improved method for producing the cephalosporin compound, characterized in that maginium chloride is used.