JPS5857438B2 - 7- dithicanphenylglycinamide -luka methyl -3- cefem -4- carbonsanyudotai no seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides a novel 7-disubstituted phenylglycinamide-
This invention relates to a method for producing a 3-methyl-3-cephem-4-carboxylic acid derivative, and its outline is shown in the formula below.

(In the formula, R means an alkyl group, and the amine group at the α-position of the starting compound (n) may be protected with a protecting group.) This is carried out by reacting -4-carboxylic acid (I) or a derivative thereof at the carboxy group with disubstituted phenylglycine (It) or a reactive derivative thereof at the carboxy group.

Derivatives at the carboxy group of 7-amino-3-methyl-3-cephem-4-carboxylic acid (I) include salts such as sodium salt, potassium salt, magnesium salt, calcium salt, and triethylamine salt, methyl ester, and ethyl ester. , flobyl ester, isopropyl ester, methyl ester, isobutyl ester, tertiary butyl ester, tertiary pentyl ester, trimethylsilyl ester, 2-mesylethyl ester, trichloromethyl ester, 2-iodoethyl ester, 2,2... 2
- IJ chloroethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester,
trityl ester, diphenylmethyl ester, bis(
methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, (1-cyclopropyl) ethyl ester, ethynyl ester, 4-hydroxy-3,5-
Examples include esters such as tertiary butyl benzyl ester and benzhydryl ester, as well as active amides, acid anhydrides, and acid halides.

The other reaction reagent, di-substituted phenylglycine, is represented by the above general formula (I), and more specifically, it is methinopethyl-probil, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl. , cyclopentyl, cyclohexyl, etc. as R.

This disubstituted phenylglycine has an amino group which is a common amine protecting group, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-=)lobenzyloxycarbonyl, 0-bromobenzyloxycarbonyl. ,
0-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl, tertiary butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3.4
-dimethoxybenzyloxycarbonyl, 4-(phenylaso)benzyloxycarbonyl, 4-(4-methoxyphenylaso)benzyloxycarbonyl, pyridine-1-oxide-2-methylcarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl ,
In addition to easy-to-leave acyl groups such as diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, ingropoxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclofurobyl ethoxycarbonyl, and 8-quinolyloxycarbonyl, trityl , 2-nitrophenylthio, 2,4-dinitrophenylthio, 2
-Hydroxybenzylidene, 2-hydroxy-5-chlorobenzilitine, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propyritine, 1-ethoxycarbonyl-2-propyritine, 3-ethoxysulfonyl-2-butylidene, 1-acetyl-2-propyritine, 1
-benzoyl-2-propyritine, 1-CN-(2-methoxyphenyl)carbamoyl ter-2-propylidene,
1-(N-(4-methoxyphenyl)carbamoyl) to 2-glopyritene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclo Groups that are easily eliminated such as xylidene (
Among these, for example, 1-methoxycarbonyl-2-propylidene is 1-methoxycarbonyl-1-propene-
2-yl), and when the amine group is protected with two carboxy groups, such as when the amine group is combined with phthalic acid to form an imide; It is also possible to use those protected with an amine protecting group other than the acyl group, or their acid salts such as hydrochlorides, hydrobromides, and hydroiodides.

Examples of reactive derivatives at the carboxy group of this disubstituted phenylglycine include acid halides, acid anhydrides,
Active amides, active esters, etc. are mentioned, and particularly commonly used ones are acid chloride, acid azide, dialkyl phosphoric acid mixed anhydride, phenyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, dibenzyl phosphoric acid mixed anhydride, /・Rogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride,
Sulfurous mixed anhydrides, thiosulfuric acid mixed anhydrides, sulfuric acid mixed anhydrides, alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, impentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydrides, Acid anhydrides such as mixed anhydrides of aromatic carboxylic acids (e.g. benzoic acid), symmetrical acid anhydrides, acid amides with imidazoles, 4-monosubstituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, cyanomethylestenobemethoxymethyl esters, vinyl ester, flopargyl ester, p
-Nitrophenyl ester, 2,4-cy-trophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthio ester, pyranyl ester, hyridyl ester, hyhericyl ester, 8
-quinolylthioester, N-N-dimethylhydroxylamine, 1-hydroxy-2(IH)-pyridone, N
Examples include esters such as esters with -hydroxyphthalimide or N-hydroxyphthalimide, and these are appropriately selected depending on the type of disubstituted phenylglycine (I[) used.

This reaction is usually carried out in a solvent.

As a solvent, acetone, dioxane, a7tonitrile,
Examples include chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, and other general organic solvents that do not participate in the reaction. Among these, hydrophilic solvents can also be used in combination with water.

When disubstituted phenylglycine (II) is used in the form of a free acid (or its salt) in this reaction, for example, N-N'-dicyclohexylcarbodiimide, N-cyclohexyl-marmorpholinoethylcarpodiimide,
N-cyclohexyl-N-(4-diethylaminocyclohexyl)carbodiimide, N-N'-diethylcarbodiimide, N-N'-diisopropylcarbodiimide, N-ethyl-mer (3-dimethylaminepropyl)
Carbodiimide, N-N-carboxy group (2-methylimidal), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite Ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, thioninoheoxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (
It is advantageous to carry out the reaction in the presence of a condensing agent such as m-sulfophenyl) isoxazolium hydroxide inner salt or (chloromethylene) dimethylammonium chloride.

The salts of di-substituted phenylglycine (II) include alkali metal salts, alkaline earth metal salts, ammonium salts, and salts with organic bases such as trimethylamine and dicyclohexylamine.

In addition, this reaction can be carried out in the presence of a base such as an alkali metal hydrogen carbonate, trialkylamine, N-1#-dialkylbenzylamine, or pyridine, and the base or the liquid one of the above-mentioned condensing agents can be used as a solvent. It can also be used.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.

In the method of this invention, when a compound in which the carboxy group is converted to its derivative during the reaction or post-treatment of the reaction is obtained as the target substance, and 7-amino-3-methyl-3-
When a derivative of cephem-4-carboxylic acid (I) at the carboxy group is used as a raw material and the desired substance is obtained as a derivative at the carboxy group, this is then subjected to an elimination reaction to convert it to the carboxy group. lead.

For this elimination reaction, all elimination methods such as reduction and hydrolysis for converting a derivative in a carboxy group into a carboxy group can be applied.

For example, in the present invention, if the derivative at the carboxyl group is an active ester, active amide, acid anhydride, halide, etc., the reaction can be performed not only under normal hydrolysis conditions but also under mild hydrolysis conditions such as contact with water. When the derivative at the carboxy group is 2-iodoethyl ester, 2,2,2-trichloroethyl ester, benzyl ester, etc., the reduction method is used, and when the derivative at the carboxy group is 4-methoxybenzyl ester, Tertiary butyl ester, tertiary pentyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3
・For 4-dimethoxybenzylestenope (1-cyclopropyl)ethyl ester, etc., an acid method is used, and for derivatives at the carboxy group, such as ethynyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Sometimes methods using anhydrous basic catalysts are respectively employed.

Here, as a method by reduction, metals such as soot, zinc, zinc amalgam, CrCl2, Cr(OAc)2
Typical examples thereof include a method using a chromium salt such as chromium salt and an acid such as acetic acid or acetic acid, and a method using catalytic reduction.

Examples of catalysts for catalytic reduction include platinum catalysts such as platinum wire, platinum sponge, platinum black, platinum oxide, and colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon, and palladium silicate. Examples include palladium catalysts such as colloidal palladium, and nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, and Urushihara nickel.

Examples of acids used in the acid method include dinic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrochloric acid, hydrofluoric acid, p-)luenesulfonic acid, trifluoromethanesulfonic acid, and hydrochloric acid.

Examples include acetic acid mixed acid.

Furthermore, examples of the basic catalyst used in the method using an anhydrous basic catalyst include sodium salt of thiophenol, lithium dimethyl copper ((CH3)2LiCu, 1), and the like.

The elimination reaction does not require any other solvent when treated with water or when a liquid reagent such as an acid is used in the reaction, but in other cases, for example, dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, Anything that does not adversely affect this reaction, such as acetone, can be used.

The temperature of the elimination reaction is not particularly limited and is appropriately selected depending on the type of compound, reagent, etc. used.

Furthermore, if a compound in which the amine group of disubstituted phenylglycine (II) is protected with a protecting group is used as a raw material, and a compound in which the amine group is protected with a protecting group is obtained as the target substance, then this is subjected to an amine protecting group elimination reaction.

The elimination reaction of the amine protecting group is carried out by conventional methods such as decomposition with an acid or catalytic reduction depending on the type of the protecting group.

Acid decomposition is one of the most frequently used methods, such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, Applicable to substituted alkylidene, substituted cycloalkylidene, etc.

The acid used varies depending on the case, but silicic acid, trifluoroacetic acid, etc., which can be easily distilled off under reduced pressure, are most often used.

When a solvent is used in acid decomposition, a hydrophilic organic solvent, water, or a mixed solvent is often used.

Catalytic reduction is applied to, for example, benzyloxycarbonyl, substituted benzyloxycarbonyl, 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.

Incidentally, this protecting group elimination reaction can also be carried out as it is without particularly isolating and purifying the compound (1) obtained by the acylation reaction.

Further, when both the reaction of introducing the derivative at the carboxyl group into the carboxyl group and the reaction of eliminating the amine protecting group are performed, either reaction may be performed first.

The target substance obtained as described above can be converted into a desired salt by a conventional method.

The target substances (e) obtained by the method of this invention are all new compounds and are useful as antibacterial substances that are stable to acids and penicillinase.

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

Example 1 (1) N-tertiary butoxycarbonyl-2-(3-mesylamino-4-hydroxyphenyl)-ri-glycine 5
．． 21.7-amino-3-methyl-3-cephem-4-
5.52 P of hydrochloride of 2,2,2-trichloroethyl ester of carboxylic acid and 174 g of 2,6-lutidine are dissolved in 180 ml of anhydrous methylene chloride.

To this was added 2.02 g of dicyclohexylcarbodiimide with stirring under water cooling, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours.

Insoluble materials in the reaction solution are removed, and solution f is concentrated under reduced pressure.

After adding ethyl acetate to the concentrate, adjust the liquid to approximately pH with dilute phosphoric acid.
Make it 2.

The ethyl acetate layer is separated, washed with water, and dried over magnesium sulfate.

Ethyl acetate was distilled off from this solution under reduced pressure, and the residue was powdered by adding isopropyl ether.
tertiary butoxycarbonyl-2-(3-mesylamino-
4-Hydroxyphenyl)-D-glycinamidocou 3
-2,2,2 of methyl-3-cephem-4-carboxylic acid
-Trichloroethyl ester 6.7! get l.

When this is crystallized from ethyl acetate, the mp185-18
Obtain the purified product at 85°C (decomposed).

Infrared absorption spectrum (nujol) ν (cln'): 1766 Nuclear magnetic resonance absorption spectrum δ (CD3)2Co (ppm): 1.40 (9
H,s) 2.16 (3H,S) 3.01 (3H,s) 3.34.3.59 (2H,AB-q,J-18Hz
) 487.5.07 (2H,AB-qSJ-12,5H
z) 5.07 (IH, d, J=4.5Hz) 5.35 (
IH, d, J=8Hz) 5.80 (IH, d, d, J=45Hz, 8Hz) 6.3~6.5 (IH,m) 6.90 (IH, d, J=8Hz) 7 .20 (IH, d, d, J=2Hz, 8Hz)7.
52 (IH, d, J=2Hz) 8.0-8.3
(2H,m) 2)7-(N-tertiary butoxycarbonyl-2-(3-
Mesylamino-4-hydroxyphenyl)-D-glycinamide 2,2,2-trichloroethyl ester of 3-methyl-3-cephem-4-carboxylic acid3. (J?
Dissolve in 9 ml of dimethylformamide.

3.5 rul of acetic acid and 2.6 ml of zinc dust are added to this under water cooling, and the mixture is stirred at the same temperature for 40 minutes.

After the reaction, the zinc dust is washed off with a small amount of dimethylformamide, and the washing liquid and the washing liquid are combined.

Ethyl acetate and dilute phosphoric acid are added to this, and the ethyl acetate layer is separated.

After washing this extract with water, it is back-extracted with an aqueous sodium hydrogen carbonate solution.

This extract is made acidic with hydrochloric acid and then extracted with ethyl acetate.

The ethyl acetate extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure.

Washing the residue with ether gives powdered 7-CN-tert-butoxycarbonyl-2-(3-mesylamino-4
-Hydroxyphenyl)-D-glycinamidocou 3-
Methyl-3-cephem-4-carboxylic acid 1.58L? get.

Infrared absorption spectrum (nujol) ν (cIrL-1): 1765 Nuclear magnetic resonance absorption spectrum δD20 +NaHCO3 (ppm): 1.40
(9HlS) 1.90 (3H1s) 3.05 (3H1s) 300.3.39 (2H, AB-q, J-18Hz) 4.90 (IH, d, J=4.5Hz) 5.08
(IH, s) 5.52 (IH, d, J=4.5Hz) 6.8-7.
4 (3H,m) (3) 7-(N-tertiary butoxycarbonyl-2-
(3-mesylamino-4-hydroxyphenyl)-D-
[gl,l cinamide]-3-methyl-3-cephem-4
-Dissolve 1.4Fl of carboxylic acid in 6ml of silicic acid,
Stir at ℃ for 1.5 hours.

After the reaction, the silicic acid was distilled off under reduced pressure, and the residue contained acetonate.
IJ le 30m1. After that, 0.5 Ttl of water is added to this while stirring, and the mixture is stirred for 30 minutes.

The precipitated powder was collected and washed sequentially with acetonitrile and ether, resulting in a 7-
(2-(3-mesylaminol 4-hydroxyphenyl)
-D-glycinamidocou-3-methyl-3-cephem-
4-carboxylic acid 1.13f is obtained.

Infrared absorption spectrum (nujol) ν ((=217Jll) 2 1760 nuclear magnetic resonance absorption spectrum δD20+DC1 (ppm): 2.12 (3H
,s) 3.20 (3H,S) 3.25.3.50 (2H,AB-q1J=18H
z ) 5.09 (IH, d, J=4.5Hz) 5.33 (
IH, s ) 5.66 (IH, d, J=4.5Hz) 7.15 (
IH, d, J=8Hz) 7.40 (IH, d, d, J=2Hz, 8Hz)7.
53 (IH, dSJ=2Hz)

Claims (1)

[Claims] 7-amino-3-methyl-3-cephem-4 represented by formula 1
- Di-substituted phenylglycine represented by the general formula (in the formula, R means an alkyl group, and the amine group at the α-position may be protected with a protecting group) in a carboxylic acid or its derivative at the carboxy group. If the reaction product is obtained as a derivative of the carboxy group or a protected product of the amine group after reacting with a reactive derivative of the carboxy group, the reaction product is then subjected to an elimination reaction to form the general formula (wherein R has the same meaning as before) 7-disubstituted phenylglycinamide-3-methyl-3-cephem-4-carboxylic acid derivative is obtained. 3-
Method for producing methyl-3-cephem-4-carboxylic acid derivative.