JPS6018672B2 - Method for producing 7-substituted phenylglycinamido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides a novel 7-substituted phenylglycisamide 3
This relates to a method for producing -alkanoyloxymethyl-3-cephemu-4-carboxylic acids, and the formula is as follows.

(In the formula, tR is an alkanoyl group, R2 is an alkyl group,
(means an amino group or a protected amino group, respectively) The carboxylic acids (0) used in this invention and their reactive derivatives at the carboxy group are new compounds, and can be produced, for example, according to the method illustrated below. .

(wherein R2 has the same meaning as before and X' means a protected amino group).
-alkanoyloxymethyl-3-cephemu-4-carboxylic acids (1) or its amino group and/or
This is carried out by reacting a carboxylic acid (b) or a reactive derivative thereof with a carboxy group on a derivative with a carboxyl group.

The 7-amino-3-alkanoyloxymethyl-3-cepheme-4-carboxylic acids (1) used in this invention are represented by the general formula (1) above, but more specifically, formyl, acetyl, propionyl, butyryl , refers to a compound having an alkanoyl group as R, such as bentanoyl. Examples of derivatives of the amino group of these 7-amino-3-alkanoyloxymethyl-3-cephem-4-carboxylic acids (1) include reaction products of compound (1) and silyl compounds such as bistrimethylsilylacetamide. , and derivatives at the carboxy group include sodium salt, potassium salt, magnesium salt,
Salts such as calcium salts and triethylamine salts, methyl ester, ethyl ester, tertiary butyl ester, tertiary
Bentyl ester, trimethylsilyl ester, 2-
Mesyl ethyl ester, triclo. methyl ester, 2
-Iodoethyl ester Y2,2,2-trichloroethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester, trityl ester, bis(methoxy phenyl) methyl ester, 3,4-dimethoxybenzyl ester,
Examples include esters such as (1-cyclopropyl)ethyl ester, ethynyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, and benzhydryl ester. The other raw material, carboxylic acids, is represented by the above-mentioned general formula (0), but more specifically, it includes alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, bentyl, hexyl, etc. It means a compound having R2 as R2 and an amino group or a protected amino group as x.

Examples of the protecting group for the amino group protected here include penzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-promobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-dimethoxybenzyloxycarbonyl, 1-(phenylazo)penzyloxycarbonyl, 4-1(4-methoxyphenylazo)penzyloxycarbonyl, tertiary ptoxycarbonyl, tertiary benzyloxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2- Pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tripromoethoxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-iodopropoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl , 8-ky/lyloxycarbonyl, trifluoroacetyl, trityl, 2-
nitrophenylthio, 2,4-dinitrophenylthio,
2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydro. xy-1naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-bropylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene,
1-propionyl-2-propylidene, 1-benzoyl-2-propylidene, 1,3-pis(ethoxycarbonyl)-2-propylidene, 1-(N-methylcarbamoyl)-2-propylidene, 1-(N,N-dimethylcarbamoyl)-2-propylidene, 1-{N-(2-methoxyphenyl)rubamoyl}-2-propylidene, 1
-{N-(4-methoxyphenyl)carbamoyl}-2
-Propylidene, 1-(N-phenylcarbamoyl)-
Examples include groups that are easily eliminated such as 2-propylidene, 2-ethoxycarbonylcyclobentridene, 2-acetylcyclohexylidene, and 3,3-dimethyl-5-oxocyclohexylidene (among these, for example, 1-methoxycarbonyl- 2-propylidene is sometimes expressed as 1-methoxycarbonyl-1-proben-2-yl; for example, 2-ethoxycarbonylcyclohexylidene is sometimes expressed as 2-ethoxycarbonyl-1-cyclohexenyl). Further, acid salts of free amino groups such as hydrochloride, hydrobromide, and hydroiodide are also exemplified as protected amino groups. These carboxylic acids (0
Examples of reactive derivatives at the carboxyl group of ) include acid halides, acid anhydrides, activated amides, activated esters, etc., but especially frequently used ones include acid chlorides, acid azides, dialkyl phosphoric acid mixed anhydrides, Phenylphosphoric acid mixed anhydride, diphenylphosphoric acid mixed anhydride, dibenzylphosphoric acid mixed anhydride, halogenated phosphoric acid mixed anhydride, dialkyl phosphoric acid mixed anhydride, sulfurous acid mixed anhydride, thiosulfuric acid mixed anhydride, sulfuric acid mixed anhydride, alkyl carbonic acid Acid anhydrides such as mixed anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, bentanoic acid, isobesotanoic acid, 2-ethylbutanoic acid, trichloroacetic acid), mixed anhydrides, symmetrical acid anhydrides, imidazole, 4-substituted imidazole, dimethyl pyrazole,
Triazole, amides with tetrazole, cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, bentachlorophenyl ester, methane Sulfonylphenyl ester, phenyl azophenyl ester, phenyl thioester, 4-nitrophenyl thioester, p-cresyl thioester, hydroxymethyl thioester, pyranyl ester, pyridyl ester, piveridyl ester, 8-quinolylthio In addition to esters such as ester, N,N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide or N-hydride. Examples include esters with xyphthalimide, and these are appropriately selected depending on the type of carboxylic acid (b) used. When carboxylic acids (0) are used in the form of a free acid or a salt thereof in this reaction, examples thereof include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'- (4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'
-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,
N'-carbonyldi(2-methylimidazole), bentamethyleneketene-N÷cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, phosphorous trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid Sopropylester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl) ) It is advantageous to carry out the reaction in the presence of a condensing agent such as inxazolium hydroxide inner salt or (chloromethylene) dimethylammonium chloride.

The salts of carboxylic acids (0) include alkali metal salts, alkali metal salts, ammonium salts, and salts with organic bases such as trimethylamine and dicyclohexylamine. This reaction is usually carried out in a solvent. Examples of solvents include general organic solvents that do not adversely affect the reaction of the present invention, such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, chloromodified ethylene, tetrahydrofuran, ethyl acetate, dimethylformamide, and pyridine. The organic solvent can also be used in combination with water. This reaction may also be carried out in the presence of a base such as an alkali metal bicarbonate, trialkylamine, N,N-dialkylbenzylamine, or pyridine, and the base or the liquid condensing agent mentioned above can also serve as a solvent. can be used. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. The reaction product is collected by a conventional method. When carrying out the above reaction using carboxylic acids (0) having a protected amine/group as The amyl/base compound is the target compound (
Although it may be obtained as m), this case is also included in this invention.

If an amine/protecting group is present in the product of the above acylation reaction, the reaction product is then subjected to an amino protecting group elimination reaction.

The elimination reaction of the amino protecting group is carried out by a commonly used method such as treatment with an acid or catalytic reduction depending on the type of the protecting group.

Elimination reaction with acid is one of the most frequently used methods.
For example, for penzyloxycarbonyl, substituted penzyloxycarbonyl, alkoxycarbonyl, di-alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene, etc. Applicable. The acid used differs depending on the case, but the most commonly used are diprotic acid, trifluoroacetic acid, etc., which can be easily distilled off under reduced pressure. When a solvent is used in acid decomposition, a hydrophilic organic solvent, water, or a mixed solvent thereof is often used. Catalytic reduction is applied to penzyloxycarbonyl, substituted penzyloxycarbonyl, 2-pyridylmethoxycarbonyl, etc., and palladium catalysts are most often used, but other catalysts can also be used. In addition, protective group elimination reactions are usually carried out by treating trifluoroacetyl with water, and treating halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl with heavy metals such as copper and zinc. . In addition, when carboxylic acids (0) in which the acid salt of a free amino group is present as a protected amino group are used as a raw material, the removal of the amino protecting group from the reaction product can be performed by converting the reaction product into trimethylamine. , triethylamine, N-methylpiverazine, N,N'-dimethylaniline, pyridine, etc., as well as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, etc. This is done by treatment with a base. The removal of these amino protecting groups can also be carried out as is without particularly isolating or purifying the reaction product. 7-substituted phenylglycinamide 3-alkanoyloxymethyl-3 thus obtained
-Cephemu-4-carboxylic acid (m) can be converted into salts with inorganic or organic bases such as sodium salt, potassium salt, triethylamine salt, dicyclohexylamine salt, etc., or salts with inorganic or organic bases such as hydrochloride, sulfate, tartrate, etc. by conventional methods. It can lead to the desired salt.

The target products (m) obtained by the method of the present invention are all new compounds and are useful as antibacterial monsters that are stable to acids and benicillinase.

Next, the method of the present invention will be explained with reference to examples. Example
1mD-N-tertiary ptoxycarbonyl-Q-(3-methylaminophenyl)glycine 9.9 g, triethylamine 3.22 g, and tetrahydrofuran 140 g.
Add at 0 and heat for 20 minutes at the same temperature.

7.87 g of 7-aminocephalosporanic acid, 3.5 g of triethylamine, 40 g of tetrahydrofuran and 4 g of water
A solution consisting of (0) was added all at once to the solution prepared above, and the solution was kept under ice for 1 hour and then at room temperature for 2 hours.

Tetrahydrofuran was removed from the reaction solution under reduced pressure, and the residue was dissolved in 100% of water. This was adjusted to pH 2.5 with 10% hydrochloric acid under cooling, and then extracted with ethyl acetate. The ethyl acetate extract is washed twice with water, dried over magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure to obtain an oily substance. When this is washed with ether, amorphous mp83-8
10.2 g of 4% (decomposed) 7-{D-N-tert-butoxycarbonyl-Q-(3-mesylaminophenyl)glycinamide}cephalosporanic acid are obtained. Infrared absorption spectrum Renudiol (Ki-1): 1780 n○aX Nuclear magnetic resonance absorption spectrum 6oMS.

-d6 (leg): 1.43 (group, s) 2.05
(thin, s) 3.03
(9th, s) 3.30-3.70 (ga) 5.06 (IH, d, J=5HZ) 5.55-5.97 (IH) 9.13-9
．． 43 (IH) 9.82
(IH)'21 7-{D obtained above
-N-tertiary butoxycarbonyl Q-(3-mesylaminophenyl)glycinamide}cephalosboranic acid 1
A solution consisting of g and 15 g of acidic acid was allowed to stand at room temperature for 3 hours.

The acidic acid was distilled off under reduced pressure from the reaction solution, and the residue was diluted with 10% of water.
After addition, wash twice with ethyl acetate. This was added to methyl lysoptyl ketone solution 3' containing ion exchange resin Amberlite LA-1 (manufactured by Organo) and stirred for 1 hour. The aqueous layer was separated, washed four times with ether, and then lyophilized to produce 7-{D-Q-(3-mesylaminophenyl)glycinamide}cephalosporan as a colorless powder with an mp of 240 minutes (decomposition). 0.63 g of acid is obtained. Infrared absorption spectrum Renujol (reduction-1): 1770 nnaX Nuclear magnetic resonance absorption spectrum 6D20 (leg): 2.07 (spot, s) 3.1
3 (3Hs)5.0
3 (IH, d, J = 5Hz) 5.23 (IH
,s) 5.70 (IH, d, J=5HZ) 7.30-7.63 (Rainbow day, m)

Claims (1)

[Claims] 1 7 represented by the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ In the formula, R_1 means an alkanoyl group)
-Amino-3-alkanoyloxymethyl-3-cephem-4-carboxylic acids or derivatives thereof at the amino group and/or carboxy group, the general formula ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (In the formula, R_2 means an alkyl group and X means an amino group or a protected amino group, respectively). When a protected amino group is present in the reaction product, it is subjected to the elimination reaction of the amino protecting group to form a general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R_1 and R_2 7-substituted phenylglycinamido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acid or its derivative at the carboxy group, represented by A method for producing amido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acids.