JPH0354106B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention involves reacting penicillin, cephalosporin, or a derivative thereof having a free carboxyl group with an alcohol in the presence of a base and cyanuric chloride at a temperature of 0 to -35°C to produce the corresponding ester. Regarding the method.

Here, penicillin or its derivatives have an acylamido group, an alkyl group, etc. at the 6-position, and 3α
A compound having a carboxy group at the position etc.
If necessary, the penum ring may have a double bond, an alkyl group, an alkylene group, a substituted thio group, etc., and the sulfur atom may have a sulfoxide, sulfone,
It may be exchanged with oxygen atom, methylene, etc.

In addition, cephalosporin or its derivatives have an acylamide side chain at the 7-position, the 3-position is unsubstituted, a so-called nucleophile, or a nucleophile-substituted methyl, and the 4-position or other It is a compound having a carboxy group at a position, and if necessary, the sulfur atom on the cephalosporin skeleton may be replaced with a sulfoxide, sulfone, oxygen atom, methylene, etc.

The above-mentioned acylamides include all acylamide groups known in the chemistry of so-called β-lactam antibiotics.

Any alcohol can be used as long as it can react with a reactive derivative of an acid to form an ester, and the reaction proceeds smoothly with alkanols, aralkanols, and phenolic alcohols. It has been proven that.

As the base, tertiary amines (trialkylamine, dimethylaniline, etc.) and aromatic bases (pyridine, picoline, lutidine, quinoline, etc.) are preferably used.

The raw materials and products of this reaction are known substances or their closely related compounds, and are useful as raw materials for the synthesis of useful compounds such as antibacterial agents.

Regarding the method of using cyanuric chloride as an acylation reagent, there are many reports regarding amidation, and there are also reports regarding esterification. However, there are no reports of applications in the field that is the subject of this invention.

All of the prior documents involve high-temperature reactions, but experiments by the present inventors have shown that unless the temperature is low, the yield decreases due to decomposition, making them industrially unusable.
Furthermore, it has been demonstrated that if the amount of base is not 4 equivalents or more, the yield decreases.

As previously mentioned, to practice this invention, the carboxylic acid compound to be esterified, the alcohol, the base, and cyanuric chloride are mixed, preferably in a solvent.

As solvents, industrially available inert organic solvents or excess amounts of the alcohols or bases mentioned above can be used. It has also been demonstrated that organic solvents such as halohydrocarbons, nitriles, acetones, ethers, and alcohols can be used.

Preferably 0.5-1.5 mol cyanuric chloride, 3-
Using 8 mol of base and 1.0 mol or more of alcohol,
In the case of -35°C to room temperature, the desired ester can be produced by reacting for 0.5 to 24 hours.

The ester produced in this way is concentrated,
It can be easily obtained by conventional methods such as filtration, extraction, and recrystallization.

The products of the present invention are useful as synthetic intermediates for various cephalosporins and the like.

Embodiments of the present invention will be explained below with reference to Examples.

Example 1 (a) 1.2 g of 7β-(2-thienylacetamido)cephalosporanic acid was dissolved in 12 ml of methanol, -
1.3g of pyridine and cyanuric chloride while cooling to 15℃
Add 0.75g and stir for 0.5 hour. The reaction solution is poured into water, and the precipitated crystals are collected, washed with water, and dried. If this is recrystallized from a methanol-ether mixture, 7β-(2-thienylacetamido)cephalosporanic acid methyl ester is obtained.
Obtain 1.0g. mp180~184℃.

(b) Dissolve 1.2 g of 7β-(2-thienylacetamido)cephalosporanic acid and 2 ml of 2,2,2-trichloroethanol in 7 ml of acetonitrile, and add 1.3 ml of pyridine and 0.75 g of cyanuric chloride while cooling to -20°C. , stir for 1.5 hours. Pour the reaction solution into water, collect the precipitated crystals, wash with water, dry, and recrystallize from ether to obtain 7β-
(2-thienylacetamide)cephalosporanic acid 2,2,2-trichloroethyl ester
Obtain 1.4g. mp117.5~120℃.

(c) Dissolve 1.2 g of 7β-(2-thienylacetamido)cephalosporanic acid and 1.5 ml of benzyl alcohol in 10 ml of acetone, and add pyridine under ice cooling.
Add 1.3 ml and 0.7 g of cyanuric chloride and stir for 5 hours. Pour the reaction solution into ice water, collect the precipitated crystals, wash with water, and dry. Recrystallization of the product from ether yields 7β-(2-thienylacetamido)cephalosporanic acid benzyl ester.
Obtain 1.2g. mp145.5~147℃.

Example 2 1.2 g of benzylpenicillin and 0.8 g of benzhydrol were dissolved in 10 ml of dichloromethane and heated to -10°C.
While cooling, add 1.2 g of pyridine and cyanuric chloride to this.
1.0g and reacted for 5 hours. The reaction solution was washed with water, dried, and dried to dryness, and the residue was recrystallized from acetone to obtain 1.5 g of benzylpenicillin benzhydryl ester. mp111.5~112.5℃.

Example 3 6β-phenylacetamidopenicillanic acid 1β
- Dissolve 0.43 g of oxide and 0.27 g of benzhydrol in 2 ml of dichloromethane, and add pyridine at -35°C.
Add 0.41 ml and 0.3 g of cyanuric chloride and react for 5 hours. The reaction solution is washed with water, dried, and dried, and the residue is recrystallized from acetone to obtain 6β-phenylacetamidopenicillanic acid benzhydryl ester.
0.76 g of 1β-oxide is obtained. mp82~86℃.

Example 4 6β-p-trioylaminopenicillanic acid 1β
- Dissolve 1.2 g of oxide in 10 ml of methanol, add 1.5 ml of pyridine under ice cooling and 10 ml of a chloroform solution of 0.8 g of cyanuric chloride, and stir for 2 hours. Pour the reaction solution into ice water, collect the precipitated crystals, and wash with water and methanol to obtain 6β-p-toluoylaminopenicillanic acid methyl ester 1β.
-1.1 g of oxide are obtained. mp152~154℃.

Example 5 1.0 g of 6β-benzamidopenicillanic acid 1β-oxide and 0.7 g of benzhydrol were dissolved in a mixture of 20 ml of acetonitrile and 2 ml of pyridine, and -10
Add 0.7 g of cyanuric chloride and stir for 2 hours while maintaining the temperature at °C. Pour the reaction mixture onto ice water and stir for 30 minutes. The precipitated crystals are filtered under reduced pressure, washed with water and a small amount of methanol, and dried to obtain 1.5 g of 6β-benzamidopenicillanic acid benzhydryl ester 1β-oxide. mp151~153℃.

Example 6 6β-p-trioylaminopenicillanic acid 1β
- Dissolve 1.3 g of oxide and 1.22 g of pyridine in 30 ml of dichloromethane, add 0.8 g of p-cresol and 0.9 g of cyanuric chloride while cooling to -30°C, and stir for 1 hour. The reaction solution is washed with water, dried, and concentrated under reduced pressure. Purify the residue by silica gel chromatography, collect the part containing the target product, and recrystallize it from a cyclomethane-methanol mixture.
1.5 g of 6β-p-toluoylaminopenicillanic acid p-tolyl ester 1β-oxide is obtained.
mp162.5~164℃.

Example 7 6α-phenoxyacetamidopenicillanic acid 1β
- Dissolve 1.1 g of oxide and 0.7 g of p-nitrobenzyl alcohol in 10 ml of dichloromethane, add 4 ml of pyridine and 0.7 g of cyanuric chloride under ice cooling, and stir for 4 hours. The reaction solution is washed with water, dried, and concentrated. If the residue is crystallized from an acetone-ether mixture, 6α-phenoxyamidopenicillanic acid p-nitrobenzyl ester 1β-oxide 0.9
get g. mp137-138℃.

Example 8 1.2 g of 6α-benzamidopenicillanic acid/1β-oxide and 0.7 g of benzyl alcohol are dissolved in 7 ml of dichloromethane, and 3.0 ml of triethylamine and 1.5 g of cyanuric chloride are added under ice cooling and stirring, followed by stirring for 2 hours. The reaction solution was washed with water, dried, and concentrated to dryness under reduced pressure. Recrystallizing the residue from a dichloromethane-ether mixture yields 6α-benzamidopenicillanic acid benzyl ester/1β-oxide.
Obtain 1.3g. mp118~120℃.

Example 9 6α-p-chlorobenzamide penicillanic acid.
Dissolve 1.0 g of 1β-oxide and 0.7 g of benzhydrol in a mixture of 20 ml of acetonitrile and 2 ml of pyridine, add 0.7 g of cyanuric chloride while keeping the temperature at -10°C, and stir for 2 hours. The precipitated crystals are collected, washed with water, and dried to obtain 1.5 g of 6α-p-chlorobenzamide penicillanic acid benzhydryl ester 1β-oxide. mp166~168℃.

Example 10 7β-benzamide-7α-methoxy-3,3-
Methylene-1-dethia-1-oxacefam-
4μ-carboxylic acid 0.76g and benzhydrol 0.93g
Dissolve in 5 ml of dioxane and add pyridine to this.
Add 0.38g and 0.29g of cyanuric chloride at -5℃,
Stir at the same temperature for 1 hour. After pouring the reaction solution into ice water and stirring, the precipitated crystals are collected, washed with water, and dried. Recrystallizing the residue from a dichloromethane-ether mixture yields 7β-benzamide-7α.
-methoxy-3,3-methylene-1-dethia-1
-Oxacefam-4α-carboxylic acid benzhydryl ester 1.08 g is obtained. mp196~198℃.

Claims (1)

[Claims] 1 Penicillin, cephalosporin or a derivative thereof having a free carboxyl group is reacted with alcohol at a temperature of -35°C to 0°C in the presence of a base and 0.7 to 1.5 mol of cyanuric chloride per 1 mol of the carboxyl group-containing compound. , a method for preparing the corresponding esters.