JPS6018673B2 - Method for producing 7-(2-substituted phenylglycinamide)cephalosporanic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel 7-(2-substituted phenylglycinamide) cephalosporanic acid derivative, which is represented by the following formula.

(In the formula, R means an alkyl group and X means a protected amino group, respectively.) The method of this invention uses cephalosporin C
The derivative at the carboxyl group at the 4-position is iminohalogenated and then iminoetherized, the resulting reaction product is treated with phenylglycine (1) or its reactive derivative at the carpoxy group, and then the reaction product is subjected to a solvolysis reaction. When the amino group of the resulting reaction product is protected, the reaction product is then subjected to an elimination reaction of the amino protecting group.

Examples of the conductor at the 4-carboxy group of cephalosporin C include methyl ester, ethyl ester, tertiary butyl ester, tertiary bentylester, trimethylsilyl ester, 2-mesylethyl ester, trichloromethyl ester, 2-iodoethyl ester, ,2,
2-chloroethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester, diphenylmethyl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3,4- In addition to esters such as dimethoxybenzyl ester, 1-cyclopropylethyl ester, ethynyl ester, 4-hydro*cy-3,5-ditertiary butylbengester, cephalosporin C and dichlorodimethylsilane or dichlorodimethoxysilane, etc. Examples include esters, amides, etc., which are reaction products with.

Iminohalogenation is at the 4-position carbo* of cephalosporin C.
This is carried out by allowing an iminohalogenating agent to act on the derivative at the silyl group.

As the iminohalogenating agent used here, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene, etc. are particularly frequently used. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under cooling. The reaction product thus obtained is then subjected to an iminoetherification reaction.

The iminoetherization reaction is carried out by reacting the above reaction product with an organic hydroxy compound or a salt thereof. Examples of the organic hydroxy compound or its salts used here include alcohols or metal alkoxides, and the alcohols include methanol ethanol, propanol, inpropyl alcohol, butanol, ethylene glycol propylene glycol, tertiary butyl Alkanols such as alcohol, or their alkyl moieties are methoxy, ethoxy, propoxy, isof. Examples include compounds substituted with alkoxy groups such as lopoxy, butoxy, and tertiary butoxy. In addition, metal alkoxides include alkali metal alkoxides such as sodium alkoxide and potassium alkoxide derived from the alcohols mentioned above, and alkali metal alkoxides such as calcium alkoxide and barium alkoxide. Examples include metal alkoxides. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to room temperature. The reaction product thus obtained is then treated with 2-substituted phenylglycine (1) or a reactive catalyst at its carboxy group.

2 One-layer phenylglycine is represented by the general formula (1) above, and more specifically, phenylglycine is methyl, ethyl, or phenylglycine.

It means a compound having as R an alkyl group such as propyl, isopropyl, butyl, isobutyl, tertiary butyl, bentyl, hexyl, etc. and having as X a protected amino group. Protective groups for the amino group protected here include penzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-promobenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)penzyloxycarbonyl, 4-methoxyphenylazo)penzyloxycarbonyl, tertiary butoxycarbonyl, tertiary Bentylcarbonyl, isof. Ropoxycarbonyl, diphenylmethoxycarbonyl, 2-
Pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tripromoethoxycarbonyl, 1-cyclopropylethoxycarbonyl,
3-iodopropoxycarbonyl, 2-furifuryloxycarbonyl, 1-adamantyloxycarbonyl, 8
- In addition to easily leaving acyl groups such as quinolyloxycarbonyl and trifluoroacetyl, trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, and 2-hydroxy -1-naphthylmethylene, 3
-Hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-buteridene, 1-acetyl-2-propylidene, 1-propionyl-2-propylidene, 1-penzoyl-2 -propylidene, 1,3-bis(ethoxycarbonyl)-2
-Propylidene, 1-(N-methylcarbamoyl)-2
-propylidene, 1-N,N-dimethylcarbamoyl)
12-propylidene, 1-{N-(2-methoxyphenyl)carbamoyl}, 12-propylidene, 1-{N(
4-methoxyphenyl)carbamoyl}-2-propylidene, 1-(N-phenylcarbamoyl)-2-propylidene, 2-ethoxycarbonylcyclobentridene,
Examples include groups that are easily demasculinized such as 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxocyclohexylidene (among these, for example, 1-methoxycarbonyl-2-propylidene is 1-methoxycarbonyl-1-proben-2). For example, 2-ethoxycarbonylcyclohexylidene is sometimes expressed as 2-ethoxycarbonyl-1-cyclohexenyl). Further, acid salts of free amino groups such as hydrochloric acid, hydrobromide, and hydroiodide are also exemplified as protected amino/groups. These 2-monosubstituted phenylglycines (
Examples of reactive derivatives at the carboxyl group in 1) include acid halides, acid anhydrides, active amides, active esters, etc., but particularly frequently used ones include acid chlorides, acid azides, alkyl carbonic acid mixed anhydrides, and fatty acids. Acid anhydrides such as group carboxylic acids (e.g. pivalic acid, bentanoic acid, isobentanoic acid, 2-ethylbutanoic acid) mixed anhydrides, aromatic carboxylic acids (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, imidazole, 4- Active acid amides with substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc., cyanomethyl esters, methoxymethyl esters, vinyl esters, 1-toxy vinyl esters, 1-ethoxy vinyl esters, pro/grugyl esters, p-nitro Phenyl ester, trichlorophenyl ester, bentachlorophenyl ester, methanesulfonylphenyl ester, phenyl azophenyl ester, phenylthioester, p-nitrophenyl thioester, p-cresyl thioester, hydroxymethyl thioester , pyranyl ester, pyridyl ester, piveridyl ester, 8-quinolylthioester, N
, N-dimethylhydroxyamine, 1-hydroxy-2
Examples include active esters such as esters with (IH)-pyridone, N-hydroxysuccinimide, or N-hydroxyphthalimide, and these are appropriately selected depending on the type of phenylglycine (1) used. Ru.

This reaction can also be carried out in the presence of an organic base, and examples of the organic base used in that case include trialkylamine, N,N-dialkylbenzylamine, and pyridine. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature to elevated temperature. In this reaction, the reaction solution from the previous reaction may be used as it is, or the reaction solution may be concentrated under reduced pressure and excess immi/halogenating agent and alcohols distilled off. good. The reaction product thus obtained is finally subjected to a solvolysis reaction.

The solvolysis reaction is carried out by adding water or an alcohol such as methanol, ethanol, propanol, butanol, inpropyl alcohol, or a mixture thereof to the reaction solution obtained in the first step. This reaction can also be carried out in the presence of an alkali metal hydrogencarbonate, a base such as a trialkylamine, or an acid such as dilute hydrochloric acid or acetic acid. The reaction product, 7-(2-substituted phenylglycinamide) cephalosporanic acid derivative (b), is isolated and collected by a conventional method. It is preferable that all reactions of this invention are carried out under anhydrous conditions except for the final solvolysis reaction. Note that depending on the type of derivative of the carboxy group of cephalosporin C and the reaction conditions, the target compound (0) having a free carboxy group may be obtained, and this case is also included in the present invention. Further, depending on the type of protecting group on the amino group of compound (0) and the reaction conditions, the target compound (b) from which the protecting group has been removed may be directly obtained, and this case is also included in the present invention. When the amino group of the product obtained by the above-mentioned solvolysis reaction is protected, the product is then subjected to an amino-protecting group elimination reaction.

The dehydrogenation reaction of the amino protecting group is carried out by conventional methods 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, applicable to penzyloxycarbonyl, substituted penzylcarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene, etc. be done. 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 performed, for example, on penzyloxycarbonyl, substituted penzyloxycarbonyl, 2-
It is applied to pyridylmethoxycarbonyl, etc., and the most frequently used catalyst is palladium, but other catalysts are also 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. . Furthermore, when the compound (1) in which a free amino acid salt of an amino group exists as a protected amino group is used as a raw material, the amino protecting group of the reaction product can be removed by converting the reaction product into trimethylamine, triethylamine, It is carried out by straining, which is treated with a tertiary organic base such as N-methylpiverazine, N,N-dimethylaniline, and pyridine, as well as bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, and ammonium carbonate. be exposed. The removal of these amino protecting groups can also be carried out as is without particularly isolating or purifying the reaction product. The thus obtained 7-(2-substituted phenylglycinamide) cephalosporanic acid derivative (b) can be prepared by a conventional method as a salt with an inorganic or organic base such as sodium salt, potassium salt, triethylamine salt, dicyclohexylamine salt, or hydrochloride. , sulfates, tartrates, and other salts with inorganic or organic acids. The objects (n) obtained by the method of this invention are all novel compounds and are useful as acid- and benicillinase-stable antibacterial substances.

Next, the method of the present invention will be explained using examples.

Example 1'1) Cephalosporin CO. 83 chloride was suspended in 20 ml of dichloromethane, and triethylamine was added to this.
．． 33 desktop, chlorotrimethylsilane 0. Isokki and N
, N-dimethylaniline (1.87 g) was added, and the mixture was incubated at room temperature for 1 hour.

Cool this to -6000 with acetone/dry ice,
Add 0.88 g of 5-phosphorus chloride while stirring strongly, and boil for 140~
I worshiped the hawk for 2 hours for 150 oo. To this, 0.11 ml of N,N-dimethylaniline and 8.25 ml of n-butanol were added, and after incubating at the same temperature for 3 minutes, the temperature was gradually increased and the flies were incubated at -15 to 1100 for 3 hours. Add 1.1 drops of N,N-dimethylaniline to this mixture at -1030 or less, and
Mixed acid anhydride of polytertiary-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycine and isobutyl chloroformate [Preparation method: N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycine aminophenyl)-D-glycine 8
To a solution consisting of 9 of 80 and 5 of methylene chloride is added 222 o of triethylamine and 1 drop of N,N-dimethylbenzylamine. This solution was added dropwise to a solution consisting of 300 parts of isobutyl chloroformate and 5 parts of methylene chloride at -15 pm over a period of 18 minutes.
5-11400 and worship for 45 minutes. ] was added dropwise over a period of 5 minutes at 115°C to 1100°C, and the mixture was allowed to stand at 110°C to 18°C for 1 hour and at room temperature for 2 hours. The solvent was removed from the reaction solution under reduced pressure, and 20 parts of ethyl acetate was added to the residue, which was then diluted with 10 parts of 3% hydrochloric acid twice, once with 10 parts of water, and 10 parts of saturated aqueous sodium bicarbonate solution.
and once with 10 ml of saturated aqueous sodium chloride solution. The organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue was subjected to silica gel column chromatography [developing solvent: ethyl acetate (10), decaacetic acid (1)], and the main effluent was concentrated to dryness under reduced pressure. Add ether to the remaining oil and rub it to solidify. When the solid content is taken out in a furnace and washed with ether, mp83-84qo (
9 of 7-{N-tert-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycinamide}cephalosporanic acid 340 is obtained in the amorphous form of (decomposition). Infrared absorption spectrum Hisagi Juru (skin 4): 1780 Nuclear magnetic resonance absorption spectrum 60MSod6 (willow): 1.43 (ban, s) 2.0
5 (so, s) 3.03 (thin, s) 3.30-3.70 (ga) 5.06 (IH, d, J = 8 ce) 5.55-5.97 (IH) 9. 13-9.43 (IH) 9.82 (IH) } 7-{D-N-tertiary-butoxycarbonyl-a-(3-mesylaminophenyl)glycinamide} cephalosporanic acid obtained above and A solution consisting of chloric acid 15 is simulated at room temperature for 3 hours.

The acidic acid was removed from the reaction solution under reduced pressure, and 10 pieces of water were added to the residue, which was then washed twice with ethyl acetate. This was added to methyl isobutyl ketone solution 3 containing ion exchange resin Amberlite LA-1 (manufactured by Organo) and left for 1 hour. After separating the aqueous layer and washing it with ether four times,
Freeze-drying yields 0.63 of D-a-(3-mesylaminophenyl)glycinamide}cephalosporanic acid as a colorless powder of mp 240 qo (degraded). Infrared absorption spectrum (leg): 1770 Nuclear magnetic resonance absorption spectrum 60 (leg): 2.07 (SH, s) 3.13 (3 days, s) 5.03 (IH, d , J=9 ce) 5.23 (IH, s) 5.70 (IH, d, J=8 ce) 7.30-7.63 (4 days, m)

Claims (1)

[Claims] 1. The derivative at the 4-position carboxy group of cephalosporin C is iminohalogenated and then iminoetherified, and the resulting reaction product has a general formula ▲a mathematical formula, a chemical formula, a table, etc.▼ (in the formula, R is 2-substituted phenylglycine represented by an alkyl group (X means a protected amino group) or a reactive derivative thereof at a carboxyl group, and then the reaction product is subjected to a solvolysis reaction to obtain a When the amino group of the reaction product is protected, the general formula ▲mathematical formula, chemical formula, table, etc. is given for the elimination reaction of the amino protecting group▼ (in the formula, R has the same meaning as before). A method for producing a 7-(2-substituted phenylglycinamide)cephalosporanic acid derivative, which is characterized in that the following 7-(2-substituted phenylglycinamide)cephalosporanic acid or a derivative thereof at the carboxy group is obtained.